Hiv inhibitor compounds

ABSTRACT

The invention provides a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof as described herin. The invention also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS symptoms in a mammal using compounds of Formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit of priority of U.S.Provisional Patent Application Ser. No. 62/455,348, filed Feb. 6, 2017.The contents of this application are incorporated herein by reference.

FIELD

The present disclosure relates to novel compounds for use in thetreatment of a Retroviridae viral infection including an infectioncaused by the HIV virus. The present disclosure also relates tointermediates for its preparation and to pharmaceutical compositionscontaining those compounds.

BACKGROUND

Human immunodeficiency virus (HIV) infection and related diseases are amajor public health problem worldwide. Human immunodeficiency virus type1 (HIV-1) encodes three enzymes which are required for viralreplication: reverse transcriptase, protease, and integrase. Severalprotease inhibitors (PI) are presently approved for use in AIDS or HIV.Yet many PI inhibitors suffer from high rates of hepatic metabolism,which may require co-administration of a booster or more frequentdosing. Furthermore, viral resistance remains a problem. Accordingly,there is a need for new agents that inhibit the replication of HIV.

SUMMARY

The present disclosure provides compounds and methods for the treatmentof an HIV infection. Accordingly, in one embodiment, the inventionprovides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selectedfrom N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5heteroatoms selected from N, O, and S, wherein the 5 to 10-memberedheterocycle or 5 to 10-membered heteroaryl is optionally substitutedwith 1 to 5 R^(a) groups;

R² and R³ are each independently C₁₋₄alkyl, C₃₋₆cycloalkyl, O—R^(2A),C₁₋₂alkyl-O—R^(2A), N-(R^(3A))₂, or C₁₋₂alkyl-N-(R^(3A))₂,

wherein each R^(2A) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N,O, and S,

wherein each R^(3A) is independently hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl, or COO(R^(e)),

and wherein each C₃₋₆cycloalkyl or 4 to 10-membered heterocyclyl isoptionally substituted by 1 to 3 R^(f) groups, wherein each R^(f) isindependently C₁₋₂alkyl or halogen;

-   R⁴ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,    C₁₋₄alkoxy, or C₁₋₄haloalkoxy;-   R⁷ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,    C₁₋₄alkoxy, or C₁₋₄haloalkoxy;-   R⁵, R⁶, R⁸, and R⁹ are each independently hydrogen, halo, C₁₋₂alkyl,    C₁₋₂haloalkyl, or C₃₋₆cycloalkyl;    -   and wherein two or more of R⁴, R⁵ and R⁶ or two or more of R⁷,        R⁸, and R⁹ optionally join together to form one or more        C₃₋₆cycloalkyl groups that are optionally substituted with 1 to        4 groups selected from halogen, C₁₋₂alkyl, and C₁₋₂haloalkyl;-   each R¹⁰ is independently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, or    C₃₋₆cycloalkyl; n is 0 to 4;-   each R^(a) is independently halogen, C₁₋₄alkyl, C₁₋₄alkyl with 1 to    2 groups selected from hydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl,    C₁₋₄alkoxy, C₃₋₆cycloalkyl, 4 to 10-membered heterocyclyl having 1    to 5 heteroatoms selected from N, O, and S which is optionally    substituted with R^(a1), or O—R^(3B),    -   wherein R^(3B) is C₃₋₆cycloalkyl optionally substituted with        R^(a1) or a 4 to 10-membered heterocyclyl having 1 to 5        heteroatoms selected from N, O, and S optionally substituted        with R^(a1),    -   wherein each R^(a1) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl,        C₁₋₄haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3        heteroatoms selected from N, O, and S;-   A is ethynyl or a bond;-   X¹ is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl    having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6    to 10-membered aryl or 5 to 10-membered heteroaryl is optionally    substituted with 1 to 4 R^(b) groups;-   X² is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5    heteroatoms selected from N, O, and S, wherein the 4 to 10-membered    heterocyclyl is optionally substituted with one R¹¹ and optionally    substituted with 1 to 5 R^(b) groups;-   R¹¹ is C═O(R^(c)), CH₂(R), S(O)₁₋₂(C₁₋₄alkyl),    S(O)₁₋₂C₃₋₆cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5    heteroatoms selected from N, O, and S, or a 5 to 9-membered    heteroaryl having 1 to 5 heteroatoms selected from N, O, and S,    wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered    heteroaryl is optionally substituted with 1 to 5 R^(b) groups;

each R^(b) is independently halogen, oxo, C₁₋₄alkyl, C₁₋₄alkyl with 1 to2 groups selected from hydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄alkoxy, or COO(R^(e));

R^(c) is C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, N(R^(e))₂,C₃₋₆cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, wherein the C₃₋₆cycloalkyl andthe 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5R^(b) groups;

R^(d) is COO(R^(e)), N(R^(e))₂, C₃₋₆cycloalkyl, or a 4 to 6-memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S,wherein the C₃₋₆ cycloalkyl and the 4 to 6-membered heterocyclyl isoptionally substituted by 1 to 5 R^(b) groups;

each R¹² is C₁₋₂alkyl, halo, —OC₁₋₂alkyl, or cyano;

each p is 0 to 4;

and each R^(e) is independently hydrogen or C₁₋₄alkyl.

Also provided is a pharmaceutical composition comprising atherapeutically effective amound of a compound disclosed herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition further comprising one, two, three, or four additionaltherapeutic agents.

Also provided is method of treating or preventing a humanimmunodeficiency virus (HIV) infection comprising administering atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, to a subject in need thereof.

In certain embodiments, the current disclosure relates to an article ofmanufacture comprising a unit dosage of a compound disclosed herein, ora pharmaceutically acceptable salt thereof.

Also provided is a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, for use in therapy.

A compound disclosed herein, or a pharmaceutically acceptable saltthereof, for use in a method of treating or preventing a humanimmunodeficiency virus (HIV) infection comprising administering atherapeutically effective amount of said compound to a subject in needthereof, is also provided.

DESCRIPTION OF THE DRAWINGS

FIG. 1 describes the hepatic predicted clearance for certain compoundsand reference compounds as more fully described in the biologicalexamples herein.

FIG. 2 describes a graph of the IV dog pharmacokinetic studies forcertain compounds and reference compounds and table summarizing IV andoral PK data for those compounds as more fully described in the examplesherein.

FIG. 3 describes a graph of the IV rat pharmacokinetic studies forcertain compounds and reference compounds and table summarizing IV andoral PK data for those compounds as more fully described in the examplesherein.

FIG. 4 describes the fold change vs. wild type for certain clinicalisolate resistance mutations for certain compounds and referencecompounds as more fully described in the examples herein.

FIG. 5 describes the resistance breakthrough for certain compounds andreference compounds as more fully described in the examples herein.

DETAILED DESCRIPTION

The following is a list of abbreviations and acronyms used throughoutthe application:

-   -   Abbreviation Meaning    -   ° C. Degree Celsius    -   ATP Adenosine-5′-triphosphate    -   AcOH Acetic acid    -   d Doublet    -   dd Doublet of doublets    -   DCE 1,2-dichloroethane    -   DCM Dichloromethane    -   DIPEA N,N-diisopropylethylamine    -   DME 1,2-dimethoxyethane    -   DMF Dimethylformamide    -   DMSO Dimethylsulfoxide    -   dppf 1,1′-Bis(diphenylphosphino)ferrocene    -   EGTA Ethylene glycol tetraacetic acid    -   ETOAC Ethyl acetate    -   equiv/eq Equivalents    -   ESI Electrospray ionization    -   Ac Acetate    -   Et Ethyl    -   g Grams    -   HATU 2-(7-Aza-1H-Benzotriazole -1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   hERG human Ether-á-go-go Related Gene    -   HPLC High-performance liquid chromatography    -   h/hr Hours    -   Hz Hertz    -   IC₅₀ The half maximal inhibitory concentration    -   J Coupling constant    -   Kg Kilogram    -   M Molar    -   m multiplet    -   m/z mass-to-charge ratio    -   M+ Mass peak    -   M+H Mass peak plus hydrogen    -   Me Methyl    -   MeOH Methyl alcohol/methanol    -   mg Milligram    -   MHz Megahertz    -   min/m Minute    -   ml/mL Milliliter    -   mM Millimolar    -   mmol Millimole    -   MS Mass spectroscopy    -   mw Microwave    -   N Normal    -   mol Mole    -   NMP N-methylpyrrolidinone    -   NMR Nuclear magnetic resonance    -   Ph Phenyl    -   ppm Parts per million    -   prep Preparative    -   Rf Retention factor    -   RP Reverse phase    -   RT/rt Room temperature    -   s Second    -   s Singlet    -   t Triplet    -   TEA Triethylamine    -   TFA Trifluoroacetic acid    -   TLC Thin layer chromatography    -   TMS trimethylsilyl    -   WT Wild type    -   δ Chemical shift    -   μm Microgram    -   μL/μl Microliter    -   μM Micromolar    -   μm Micrometer    -   μmol Micromole

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

A dash at the front or end of a chemical group is a matter ofconvenience; chemical groups may be depicted with or without one or moredashes without losing their ordinary meaning. A wavy line drawn througha line in a structure indicates a point of attachment of a group, e.g.

A dashed line indicates an optional bond. Where multiple substituentgroups are identified the point of attachment is at the terminalsubstituent (e.g. for “alkylaminocarbonyl” the point of attachment is atthe carbonyl substituent).

The prefix “C_(x-y)” indicates that the following group has from x(e.g. 1) to y (e.g. 6) carbon atoms, one or more of which, in certaingroups (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, etc), may bereplaced with one or more heteroatoms or heteroatomic groups. Forexample, “C₁₋₆alkyl” indicates that the alkyl group has from 1 to 6carbon atoms. Likewise, the term “x-y membered” rings, wherein x and yare numerical ranges, such as “3 to12-membered heterocyclyl”, refers toa ring containing x-y atoms (e.g. 3-12), of which up to 80% may beheteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “arylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”refers to the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), and/or(Ie). Also included are the specific compounds of Examples 1-245.

“Alkyl” refers to any group derived from a linear or branched saturatedhydrocarbon. Alkyl groups include, but are not limited to, methyl,ethyl, propyl such as propan-1-yl, propan-2-yl (iso-propyl), butyls suchas butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (iso-butyl),2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, dectyls, andthe like. Unless otherwise specified, an alkyl group has from 1 to 10carbon atoms, for example from 1 to 6 carbon atoms, for example from 1to 4 carbon atoms.

“Alkenyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon double bond. Alkenyl groupsinclude, but are not limited to, ethenyl (vinyl), propenyl (allyl),1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, analkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6carbon atoms, for example from 2 to 4 carbon atoms.

“Alkynyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon triple bond and includesthose groups having one triple bond and one double bond. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡C—),propargyl (—CH₂C≡C—), (E)-pent-3-en-1-ynyl, and the like. Unlessotherwise specified, an alkynyl group has from 2 to 10 carbon atoms, forexample from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.

“Amino” refers to —NH₂. Amino groups may also be substituted asdescribed herein, such as with alkyl, carbonyl or other amino groups.The term “alkylamino” refers to an amino group substituted with one ortwo alkyl substituents (e.g. dimethylamino or propylamino).

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis also to be understood that when reference is made to a certainatom-range membered aryl (e.g., 6-10 membered aryl), the atom range isfor the total ring atoms of the aryl. For example, a 6-membered arylwould include phenyl and a 10-membered aryl would include naphthyl and1, 2, 3, 4-tetrahydronaphthyl. Aryl groups include, but are not limitedto, those groups derived from acenaphthylene, anthracene, azulene,benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene,fluorene, indane, perylene, phenalene, phenanthrene, pyrene and thelike. Non-limiting examples of aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl,anthracenyl, and the like.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as an alkylenyl orheteroalkylenyl group or a single heteroatom. Quinuclidinyl andadmantanyl are examples of bridged ring systems.

The term “cycloalkyl” refers to a single saturated or partiallyunsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e.,C₃₋₂₀ cycloalkyl), for example from 3 to 12 annular atoms, for examplefrom 3 to 10 annular atoms. The term “cycloalkyl” also includes multiplecondensed, saturated and partially unsaturated all carbon ring systems(e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).Accordingly, cycloalkyl includes multicyclic carbocyles such as abicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 annular carbon atoms). Therings of a multiple condensed ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,spiro[3.3]heptane, and 1-cyclohex-3-enyl.

“Halo” and “halogen” refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to an alkyl wherein one or more hydrogen atoms areeach replaced by a halogen. Examples include, but are not limited to,—CH₂Cl, —CH₂F, —CH₂Br, —CFClBr, —CH₂CH₂Cl, —CH₂CH₂F, —CF₃, —CH₂CF₃,—CH₂CCl₃, and the like, as well as alkyl groups such as perfluoroalkylin which all hydrogen atoms are replaced by fluorine atoms.

“Alkoxy” or “alkoxyl” refers to a moiety of the formula -O-alkyl,wherein the alkyl portion is as defined above. For example, C₁₋₄alkoxyrefers to a moiety having 1-4 carbon alkyl group attached to the oxygen.“Haloalkoxy” or “haloalkoxyl” refers to a moiety of the formula-O-haloalkyl, wherein the haloalkyl portion is as defined above. Forexample, C₁₋₄alkoxy refers to a moiety having 1-4 carbon halo alkylgroup attached to he oxygen.

“Heteroalkyl” refers to an alkyl in which one or more of the carbonatoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatom or heteroatomic ngroup.Heteroatoms include, but are not limited to, N, P, O, S, etc.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—PH—, —P(O)₂—, —S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl,cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. Heteroalkylgroups include, but are not limited to, —OCH₃, —CH₂OCH₃, —SCH₃,—CH₂SCH₃, —NRCH₃, —CH₂NRCH₃, —CH₂OH and the like, where R is hydrogen,alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may beoptionally substituted. A heteroalkyl group comprises from 1 to 10carbon and up to four three hetero atoms, e.g., from 1 to 6 carbon andfrom 1 to 2 hetero atoms.

“Heteroaryl” refers to mono or multicyclic aryl group in which one ormore of the aromatic carbon atoms (and any associated hydrogen atoms)are independently replaced with the same or different heteroatom orheteroatomic group, as defined above. Multicyclic ring systems areincluded in heteroaryl and may be attached at the ring with theheteroatom or the aryl ring. Heteroaryl groups include, but are notlimited to, groups derived from acridine, benzoimidazole,benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole,carboline, cinnoline, furan, imidazole, imidazopyridine, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolizine,quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.Heteroaryl groups may have 5-12 members, 5-10 members, or 5-6 members.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from oxygen,nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl grouphas from 5 to about 20 annular atoms, for example from 3 to 12 annularatoms, for example from 3 to 10 annular atoms, for example from 5 to 10annular atoms or for example from 5 to 6 annular atoms. Thus, the termincludes single saturated or partially unsaturated rings (e.g., 3, 4, 5,6 or 7-membered rings) having from about 1 to 6 annular carbon atoms andfrom about 1 to 3 annular heteroatoms selected from the group consistingof oxygen, nitrogen and sulfur in the ring. The rings of the multiplecondensed ring (e.g. bicyclic heterocyclyl) system can be connected toeach other via fused, spiro and bridged bonds when allowed by valencyrequirements. Heterocycles include, but are not limited to, groupsderived from azetidine, aziridine, imidazolidine, morpholine, oxirane(epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine,pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene,dihydropyridine, tetrahydropyridine, tetrahydro-2H-thiopyran1,1-dioxide, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, andthe like. Heterocycles include spirocycles, such as, for example, aza oroxo-spiroheptanes. Heterocyclyl groups also include partiallyunsaturated ring systems containing one or more double bonds, includingfused ring systems with one aromatic ring and one non-aromatic ring, butnot fully aromatic ring systems. Examples include dihydroquinolines,e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g.1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc.,indoline, isoindoline, isoindolones (e.g. isoindolin-1-one), isatin,dihydrophthalazine, quinolinone,spiro[cyclopropane-1,1′-isoindolin]-3′-one, and the like. Additionalexamples of heterocycles include 3,8-diazabicyclo[3.2.1]octanyl,2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl,3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl, for example.

“Hydroxyl” and “hydroxy” are used interchangeably and refer to —OH.“Oxo” refers to

Where tautomeric forms of the compound exist, hydroxyl and oxo groupsare interchangeable.

It is understood that combinations of chemical groups may be used andwill be recognized by persons of ordinary skill in the art. Forinstance, the group “hydroxyalkyl” would refer to a hydroxyl groupattached to an alkyl group. A great number of such combinations may bereadily envisaged. Additional examples of substituent combinations usedherein include: C₁₋₆alkylamiocarbonyl (e.g. CH₃CH₂NHC(O)—)C₁₋₆alkoxycarbonyl (e.g. CH₃O—C(O)—), 5-7 memberedheterocyclyl-C₁₋₆alkyl (e.g. piperazinyl-CH₂—), C₁₋₆alkylsulfonyl-5-7membered heterocyclyl (e.g. CH₃S(O)₂-morpholinyl-), 5-7 memberedheterocyclyl C₁₋₆alkoxy 5-7 membered heterocyclyloxy, (4-7 memberedheterocyclyl)-4-7 membered heterocyclyl (e.g. oxetanyl-pyrrolidinyl-),C₃₋₆cycloalkylaminocarbonyl (e.g. cyclopropyl-NH—C(O)—), 5-7 memberedheterocyclyl-C₂₋₆alkynyl (e.g. N-piperazinyl-CH₂C≡CCH₂), andC₆₋₁₀arylaminocarbonyl (e.g. phenyl-NH—C(O)—).

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents. When substituents (R-groups)join together (e.g. when R⁷ and R⁸ join together) they may be taken fromthe same point of attachment to form a spiro ring.

The phrase “meta (3) position with respect to the point of attachment ofthe A ring”, refers to the position on the ring where the substituent(e.g. —CN) is adjoined and is shown below with an arrow, wherein zrepresents a carbon atom or nitrogen:

Similarly, para (4) position substitution refers to attachment of asubstituent at the position indicated below, with respect to the pointof attachment (e.g. of the B ring):

Similarly, ortho or 2-position refers to attachment of a substituent atthe position indicated below, with respect to the point of attachment:

The compounds described herein include isomers, stereoisomers and thelike. As used herein, the term “isomers” refers to different compoundsthat have the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “astereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture.

The absolute stereochemistry is specified according to the—Cahn—Ingold—Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. The presentinvention is meant to include all such possible isomers, includingracemic mixtures, optically pure forms and intermediate mixtures.Optically active (R)- and (S)- isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.If the compound contains a double bond, the substituent may be E or Zconfiguration. If the compound contains a disubstituted cycloalkyl, thecycloalkyl substituent may have a cis- or trans-configuration. Alltautomeric forms are also intended to be included. To the extent thatcompounds depicted herein are represented as having a particularstereochemistry, it is understood by one of skill in the art that suchcompounds may contain some detectable or undetectable levels ofcompounds sharing the same structure, but having differentstereochemistry.

“IC₉₅” or “EC₉₅” refers to the inhibitory concentration required toachieve 95% of the maximum desired effect, which in many cases here isthe inhibition of the HIV virus. This term is obtained using an in vitroassay evaluating the concentration-dependent inhibition of wild type HIVvirus.

“IC₅₀” or “EC₅₀” refers to the inhibitory concentration required toachieve 50% of the maximum desired effect, which in many cases here isthe inhibition of the HIV virus. This term is obtained using an in vitroassay evaluating the concentration-dependent inhibition of wild type HIVvirus.

“IQ” or “inhibitory quotient” refers to the ratio between the troughdrug concentration (C_(tau)) and level of drug resistance of the HIVisolate as determined by the IC₉₅ (i.e. C_(tau)/IC₉₅).

“Pharmaceutically acceptable” refers to compounds, salts, compositions,dosage forms and other materials which are useful in preparing apharmaceutical composition that is suitable for veterinary or humanpharmaceutical use.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Such salts include acid addition salts formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonicacid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid,oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid,tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and thelike, and salts formed when an acidic proton present in the parentcompound is replaced by either a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as diethanolamine, triethanolamine, N-methylglucamineand the like. Also included in this definition are ammonium andsubstituted or quaternized ammonium salts. Representative non-limitinglists of pharmaceutically acceptable salts can be found in S. M. Bergeet al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Scienceand Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott,Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5,both of which are hereby incorporated by reference herein.

The present disclosure also provides for prodrugs of the compoundsdisclosed herein. A “prodrug” is defined in the pharmaceutical field asa biologically inactive derivative of a drug that upon administration tothe human body is converted to the biologically active parent drugaccording to some chemical or enzymatic pathway.

“Subject” and “subjects” refers to humans, domestic animals (e.g., dogsand cats), farm animals (e.g., cattle, horses, sheep, goats and pigs),laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs,pocket pets, rabbits, dogs, and monkeys), and the like.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition);and/or c) relieving the disease or condition, e.g., causing theregression of clinical symptoms, ameliorating the disease state,delaying the progression of the disease, increasing the quality of life,and/or prolonging survival.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or subject being treated. Asis evident to one skilled in the art, a sufficient or significant delaycan, in effect, encompass prevention, in that the subject does notdevelop the disease or condition. For example, a method that “delays”development of AIDS is a method that reduces the probability of diseasedevelopment in a given time frame and/or reduces extent of the diseasein a given time frame, when compared to not using the method. Suchcomparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming a subject's HIV⁺status and assessing the subject's T-cell count or other indication ofAIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present in subjectswith functioning immune systems but does occur in AIDS patients).Development may also refer to disease progression that may be initiallyundetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, the term “preventing HIV infection”refers to administering to a subject who does not have a detectable HIVinfection an anti-HIV therapeutic substance. It is understood that thesubject for anti-HIV preventative therapy may be an individual at riskof contracting the HIV virus. Further, it is understood that preventionmay not result in complete protection against onset of the disease ordisorder. In some instances, prevention includes reducing the risk ofdeveloping the disease or disorder. The reduction of the risk may notresult in complete elimination of the risk of developing the disease ordisorder.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease or to an amount thatis effective to protect against the contracting or onset of a disease.The effective amount will vary depending on the compound, the disease,and its severity and the age, weight, etc., of the subject to betreated. The effective amount can include a range of amounts. As isunderstood in the art, an effective amount may be in one or more doses,i.e., a single dose or multiple doses may be required to achieve thedesired treatment outcome. An effective amount may be considered in thecontext of administering one or more therapeutic agents, and a singleagent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any co-administeredcompounds may optionally be lowered due to the combined action (e.g.,additive or synergistic effects) of the compounds.

The compounds of the invention include solvates, hydrates, tautomers,stereoisomers and salt forms thereof.

Provided are also compounds in which from 1 to n hydrogen atoms attachedto a carbon atom may be replaced by a deuterium atom or D, in which n isthe number of hydrogen atoms in the molecule. As known in the art, thedeuterium atom is a non-radioactive isotope of the hydrogen atom. Suchcompounds exhibit may increase resistance to metabolism, and thus may beuseful for increasing the half-life of the compounds when administeredto a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies ofDrug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogen atoms havebeen replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosedcompounds also include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. Substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds of Formula (Ia) or (Ib), can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the Examples as set out belowusing an appropriate isotopically-labeled reagent in place of thenon-labeled reagent previously employed.

As referenced herein, darunavir is a HIV protease inhibitor having thestructure:

and having the IUPAC name[(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate.Darunavir (DRV) is marketed under the brand name PREZISTA®.

As referenced herein, atazanavir is a HIV protease inhibitor having thestructure:

and having the IUPAC name methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(4-pyridin-2-ylphenyl)methyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate.Atazanavir (ATV) is marked under the brand name REYATAZ®.

Compounds

In certain embodiments, a compound of Formula I is provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selectedfrom N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5heteroatoms selected from N, O, and S, wherein the 5 to 10-memberedheterocycle or 5 to 10-membered heteroaryl is optionally substitutedwith 1 to 5 R^(a) groups;

R² and R³ are each independently C₁₋₄alkyl, C₃₋₆cycloalkyl, O—R^(2A),C₁₋₂alkyl-O—R^(2A), N-(R^(3A))₂, or C₁₋₂alkyl-N-(R^(3A))₂,

wherein each R^(2A) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N,O, and S,

wherein each R^(3A) is independently hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl, or COO(R^(e)),

and wherein each C₃₋₆cycloalkyl or 4 to 10-membered heterocyclyl isoptionally substituted by 1 to 3 R^(f) groups, wherein each R^(f) isindependently C₁₋₂alkyl or halogen;

-   R⁴ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,    C₁₋₄alkoxy, or C₁₋₄haloalkoxy;-   R⁷ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,    C₁₋₄alkoxy, or C₁₋₄haloalkoxy;-   R⁵, R⁶, R⁸, and R⁹ are each independently hydrogen, halo, C₁₋₂alkyl,    C₁₋₂haloalkyl, or C₃₋₆cycloalkyl;    -   and wherein two or more of R⁴, R⁵ and R⁶ or two or more of R⁷,        R⁸, and R⁹ optionally join together to form one or more        C₃₋₆cycloalkyl groups that are optionally substituted with 1 to        4 groups selected from halogen, C₁₋₂alkyl, and C₁₋₂haloalkyl;-   each R¹⁰ is independently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, or    C₃₋₆cycloalkyl; n is 0 to 4;-   each R^(a) is independently halogen, C₁₋₄alkyl, C₁₋₄alkyl with 1 to    2 groups selected from hydroxyl and C₁₋₄ alkoxy, C₁₋₄haloalkyl,    C₁₋₄alkoxy, C₃₋₆cycloalkyl, 4 to 10-membered heterocyclyl having 1    to 5 heteroatoms selected from N, O, and S which is optionally    substituted with R^(a1), or O—R^(3B),    -   wherein R^(3B) is C₃₋₆cycloalkyl optionally substituted with        R^(a1) or a 4 to 10-membered heterocyclyl having 1 to 5        heteroatoms selected from N, O, and S optionally substituted        with R^(a1),    -   wherein each R^(a1) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl,        C₁₋₄haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3        heteroatoms selected from N, O, and S;-   A is ethynyl or a bond;-   X¹ is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl    having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6    to 10-membered aryl or 5 to 10-membered heteroaryl is optionally    substituted with 1 to 4 R^(b) groups;-   X² is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5    heteroatoms selected from N, O, and S, wherein the 4 to 10-membered    heterocyclyl is optionally substituted with one R^(H) and optionally    substituted with 1 to 5 R^(b) groups;-   R¹¹ is C═O(R^(c)), CH₂(R^(d)), S(O)₁₋₂(C₁₋₄alkyl),    S(O)₁₋₂C₃₋₆cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5    heteroatoms selected from N, O, and S, or a 5 to 9-membered    heteroaryl having 1 to 5 heteroatoms selected from N, O, and S,    wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered    heteroaryl is optionally substituted with 1 to 5 R^(b) groups;-   each R^(b) is independently halogen, oxo, C₁₋₄alkyl, C₁₋₄alkyl with    1 to 2 groups selected from hydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl,    C₁₋₄ alkoxy, or COO(R^(e));

R^(c) is C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, N(R^(e))₂,C₃₋₆cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, wherein the C₃₋₆cycloalkyl andthe 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5R^(b) groups;

R^(d) is COO(R^(e)), N(R^(e))₂, C₃₋₆cycloalkyl, or a 4 to 6-memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S,wherein the C₃₋₆cycloalkyl and the 4 to 6-membered heterocyclyl isoptionally substituted by 1 to 5 R^(b) groups;

each R¹² is C₁₋₂alkyl, halo, —OC₁₋₂alkyl, or cyano;

each p is 0 to 4;

and each R^(e) is independently hydrogen or C₁₋₄alkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula (Ia):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X¹, and X² are as definedherein and R^(10a) and R^(10b) are independently halogen, cyano,C₁₋₄alkoxy, C₁₋₆alkyl, or C₃₋₆cycloalkyl.

In certain embodiments, the compound of Formula I or Formula (Ia) is acompound of Formula (Ib)

wherein: Z¹ and Z² are independently N or CH; m is 0 to 2, R^(10a) andR^(10b) are independently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, orC₃₋₆cycloalkyl, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and X² are asdefined herein.

In certain embodiments, the compound of Formula I, (Ia), or (Ib), is acompound of Formula (Ic):

wherein Z¹ and Z² are independently N or CH, R^(10a) and R^(10b) areindependently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, or C₃₋₆cycloalkyl,and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹, are as defined herein.

In certain embodiments, the compound of Formula I or (Ia) is a compoundof Formula (Id):

wherein R^(10a) and R^(10b) are independently halogen, cyano,C₁₋₄alkoxy, C₁₋₆alkyl, or C₃₋₆cycloalkyl, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, X¹ and X² are as defined herein.

In certain embodiments, the compound of Formula I or (Ia) is a compoundof Formula (Ie):

wherein R¹, R^(a), R¹¹, X¹ and X² are as defined herein.

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic) or(Id), R⁴ and R⁷ may be the same or different. In certain embodiments ofa compound of Formula (I), (Ia), (Ib), (Ic) or (Id), R⁴ is hydrogen,C₁₋₄alkyl, or C₁₋₄haloalkyl. In certain embodiments, R⁴ isC₁₋₄haloalkyl. In certain embodiments of a compound of Formula (I),(Ia), (Ib), (Ic) or (Id), R⁴ is CF₃. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic) or (Id), R⁷ is hydrogen,C₁₋₄alkyl, or C₁₋₄haloalkyl. In certain embodiments of a compound ofFormula (I), (Ia), (Ib), (Ic) or (Id), R⁷ is C₁₋₄haloalkyl. In certainembodiments, R⁷ is CF₃. In certain embodiments of a compound of Formula(I), (Ia), (Ib), (Ic) or (Id), R⁴ and R⁷ are CF₃ or methyl. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), R⁵,R⁶, R⁸, and R⁹ may be the same or different. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic) or (Id), R⁵, R⁶, R⁸, and R⁹are each independently hydrogen, halo, C₁₋₂alkyl, C₁₋₂haloalkyl, orC₃₋₆cycloalkyl. In certain embodiments of a compound of Formula (I),(Ia), (Ib), (Ic) or (Id), R⁵, R⁶, R⁸, and R⁹ are hydrogen, methyl, orflouro. In certain embodiments of a compound of Formula (I), (Ia), (Ib),(Ic) or (Id), R⁵ and R⁶ are C₁₋₂alkyl. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic) or (Id), R⁵ and R⁶ are methyl.In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic) or(Id), R⁸ and R⁹ are C₁₋₂alkyl. In certain embodiments of a compound ofFormula (I), (Ia), (Ib), (Ic) or (Id), R⁸ and R⁹ are methyl. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), twoor more of R⁴, R⁵, and R⁶ or R⁷, R⁸, and R⁹ may join together to formone or more C₃₋₆cycloalkyl groups that are optionally substituted withhalogen.

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), R¹ is a 5 to 6-membered heterocycle having 1 to 3heteroatoms selected from N, O, and S, or a 5 to 6-membered heteroarylhaving 1 to 3 heteroatoms selected from N, O, and S, wherein the 5 to6-membered heterocycle or 5 to 6-membered heteroaryl is optionallysubstituted with 1 to 3 R^(a) groups. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R¹ is a 5 to6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, andS and is optionally substituted with 1 to 3 R^(a) groups. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or(Ie), R¹ is:

In certain embodiments, R¹ is

In certain embodiments, R¹ is

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), R^(a) is independently C₁₋₄alkyl, C₁₋₄alkyl with 1 to 2groups selected from hydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl, or a 4 to8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O,and S optionally substituted with R^(a1). In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R^(a) isindependently C₁₋₄alkyl, C₁₋₄alkyl with 1 to 2 groups selected fromhydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl, furanyl, oxetanyl, or3,8-diazabicyclo[3.2.1]octanyl optionally substituted with R^(a1). Incertain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id)or (Ie), R^(a) is independently C₁₋₄alkyl, C₁₋₄alkyl with 1 to 2 groupsselected from hydroxyl and C₁₋₄alkoxy, or C₁₋₄haloalkyl. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or(Ie), R^(a) is:

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), R^(a) is C₁₋₄haloalkyl. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R^(a) is:

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie) R^(a) may be substituted by R^(a1). In certain embodimentsof a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R^(a) issubstituted with one R^(a1) group. In certain embodiments of a compoundof Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R^(a1) is C₁₋₄alkyl,C₃₋₆cycloalkyl, C₁₋₄haloalkyl, or 4 to 8-membered heterocyclyl having 1to 3 heteroatoms selected from N, O, and S. In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), the 4 to8-membered heterocyclyl contains 1 to 2 nitrogen heteroatoms or 1 to 2oxygen atoms.

In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X¹is a 6-membered aryl or a 5 to 6-membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S, wherein each 6-membered aryl or 5to 6-membered heteroaryl is optionally substituted with 1 to 4 R^(b)groups. In certain embodiments of a compound of Formula (I), (Ia), or(Ie), X¹ is pyrimidine or pyridine optionally substituted with 1 to 4R^(b) groups. In certain embodiments of a compound of Formula (I), (Ia),or (Ie), X¹ is pyrimidine or pyridine. In certain embodiments of acompound of Formula (I), (Ia), or (Ie), X¹ is:

In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X¹is

In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X¹is

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or(Ie), X² is a 4 to 10-membered heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S and is optionally substituted with one R¹¹ andoptionally substituted with 1 to 5 R^(b) groups. In certain embodiments,X² may be substituted by R¹¹ and R^(b). In certain embodiments of acompound of Formula (I), (Ia), (Ib), (Id) or (Ie) X² is:

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or(Ie), X² is:

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or(Ie), X² is:

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or(Ie) X² is

wherein:

a) R^(P1), R^(P2), R^(P3), and R^(P4) are each hydrogen;

b) R^(P1) and R^(P3) are taken together to form a —CH₂— or —CH₂CH₂—group and R^(P2) and R^(P4) are each hydrogen;

c) R^(P2) and R^(P4) are taken together to form a —CH₂— or —CH₂CH₂—group and R^(P1) and R^(P3) are each hydrogen.

d) R^(P1) and R^(P4) are taken together to form a —CH₂— group and R^(P2)and R^(P3) are each hydrogen; or

e) R^(P2) and R^(P3) are taken together to form a —CH₂— group and R^(P1)and R^(P4) are each hydrogen.

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or(Ie) X² is

wherein:

R^(P1) and R^(P3) are taken together to form a —CH₂— or —CH₂CH₂— groupand R^(P2) and R^(P4) are each hydrogen; or

R^(P2) and R^(P4) are taken together to form a —CH₂— or —CH₂CH₂— groupand R^(P1) and R^(P3) are each hydrogen.

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), X² is optionally substituted by R¹¹. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or(Ie), R¹¹ is 4 to 10-membered heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S. In certain embodiments of a compound ofFormula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R¹¹ is a 4 to 6-memberedheterocycle having one oxygen. In certain embodiments of a compound ofFormula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R¹¹ is oxetanyl,tetrahydrofuranyl, or tetrahydropyranyl. In cerntain embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R¹¹ isoxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),or (Id), R² and R³ may be the same or different. In certain embodimentsof a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R² and R³ areeach independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or O—R^(2A), whereinR^(2A) is C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4 to 10-membered heterocyclylhaving 1 to 5 heteroatoms selected from N, O, and S. In certainembodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R²and R³ are each independently

In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic),or (Id), R² and R³ are each methoxy.

In certain embodiments of a compound of Formula (I), each R¹⁰ may be thesame or different when n is greater than one. In some embodiments of acompound of Formula (I), (Ia), (Ib), (Ic), or (Id), n=0, 1, or 2. Incertain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or(Id), each R¹⁰ is, halogen. In certain embodiments, each R¹⁰ is, chloroor flouro.

In certain embodiments of a compound of Formula (Ia), (Ib), (Ic), or(Id), R^(10a) and R^(10b) may be the same or different. In certainembodiments of a compound of Formula (Ia), (Ib), (Ic), or (Id), R^(10a)and R^(10b) are each halogen. In certain of a compound of Formula (Ia),(Ib), (Ic), or (Id), R^(10a) and R^(10b) are each chloro or flouro.

In certain embodiments of compound of Formula I, A is ethynyl. Incertain embodiments of a compound of Formula I, A is a bond.

In certain embodiments, whenever present, each of X¹ and X² may besubstituted by one or more R^(b) groups. In certain embodiments, eachR^(b) is independently halogen, oxo, C₁₋₄alkyl, C₁₋₄alkyl with 1 to 2groups selected from hydroxyl and C₁₋₄ alkoxy, C₁₋₄haloalkyl,C₁₋₄alkoxy, or COO(R^(e)). In certain embodiments, each R^(b) isindependently oxo or halo.

In certain embodiments of a compound of Formula I, each R¹² isC₁₋₂alkyl, halo, —OC₁₋₂alkyl or cyano. In certain embodiments of acompound of Formula I, R¹² is flouro, chloro, or methyl.

In certain embodiments of a compound of Formula (Ib) or (Ic), one of Z¹and Z² is N and the other is CH. In certain embodiments of a compound ofFormula (Ib) or (Ic), both of Z¹ and Z² are N.

As disclosed above, any of the definitions for the variables provided(e.g. A, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(10a), R^(10b), Z¹,Z², X¹and X²) may be combined and grouped with other variables, whetheror not specifically recited together.

In certain embodiments of a compound of Formula (Ia), R¹ is

R^(a) is C₁₋₄haloalkyl; X¹ is pyrimidine or pyridine, R² and R³ are eachmethoxy, R⁴ is CH₃ or CF₃, R⁷ is CH₃ or CF₃, R⁵, R⁶, R⁸, and R⁹ are eachmethyl, X² is:

R10a and R^(10b) are each halogen; and R¹¹ is a 4 to 6-memberedheterocycle having one oxygen.

In certain embodiments of a compound of Formula (Ib), R¹ is

R^(a) is C₁₋₄haloalkyl; m is 0, Z¹ and Z² are independently N or CH, R²and R³ are each methoxy, R⁴ is CH₃ or CF₃, R⁷ is CH₃ or CF₃, R⁵, R⁶, R⁸,and R⁹ are each methyl; X² is:

R^(10a) and R^(10b) are each halogen; and R¹¹ is a 4 to 6-memberedheterocycle having one oxygen.

In certain embodiments of a compound of Formula (Ic), R¹

R^(a) is C₁₋₄haloalkyl; Z¹ and Z² are independently N or CH, R² and R³are each methoxy, R⁴ is CH₃ or CF₃, R⁷ is CH₃ or CF₃, R⁵, R⁶, R⁸, and R⁹are each methyl; R^(10a) and R^(10b) are each halogen; and R¹¹ isoxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

In certain embodiments of a compound of Formula (Id), R¹ is

R^(a) is —CHF₂; X¹ is pyrimidine or pyridine, R² and R³ are eachmethoxy, R⁴ is CH₃ or CF₃, R⁷ is CH₃ or CF₃, R⁵, R⁶, R⁸, and R⁹ are eachmethyl, X² is:

and R^(10a) and R^(10b) are each halogen, and R¹¹ is oxetanyl,tetrahydrofuranyl, or tetrahydropyranyl.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compouns is a compound of any of Examples1-245, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

is or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

Methods of Treatment

The pharmaceutical compositions of compounds of Formual (I) (includingcompounds of Formulae (Ia)-(Ie) may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

In one aspect, the compounds described herein may be administeredorally. Oral administration may be via, for example, capsule or entericcoated tablets. In making the pharmaceutical compositions that includeat least one compound of Formula (I), or a pharmaceutically acceptablesalt, is usually diluted by an excipient and/or enclosed within such acarrier that can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be in the formof a solid, semi-solid, or liquid material (as above), which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of Formula (I), or apharmaceutically acceptable salt, can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the subject by employing procedures known in the art.Controlled-release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions may, in some embodiments, be formulated in a unitdosage form. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient (e.g., a tablet, capsule,ampoule). The compounds are generally administered in a pharmaceuticallyeffective amount. In some embodiments, for oral administration, eachdosage unit contains from about 10 mg to about 1000 mg of a compounddescribed herein, for example from about 50 mg to about 500 mg, forexample about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450mg, about 475 mg, or about 500 mg. In other embodiments, for parenteraladministration, each dosage unit contains from 0.1 to 700 mg of acompound a compound described herein. It will be understood, however,that the amount of the compound actually administered usually will bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered and its relativeactivity, the age, weight, and response of the individual subject, andthe severity of the subject's symptoms.

In certain embodiments, dosage levels may be from 0.1 mg to 100 mg perkilogram of body weight per day, for example from about 1 mg to about 50mg per kilogram, for example from about 5 mg to about 30 mg perkilogram. Such dosage levels may, in certain instances, be useful in thetreatment of the above-indicated conditions. In other embodiments,dosage levels may be from about 10 mg to about 2000 mg per subject perday. The amount of active ingredient that may be combined with thevehicle to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms may contain from 1 mg to 1000 mg of an active ingredient.

The compounds disclosed herein, or a pharmaceutically acceptable saltthereof, may be administered to a subject in accordance with aneffective dosing regimen for a desired period of time or duration, suchas at least about one day, at least about one week, at least about onemonth, at least about 2 months, at least about 3 months, at least about4 months, at least about 6 months, or at least about 12 months orlonger. In one variation, the compound is administered on a daily orintermittent schedule. In one variation, the compound is administered ona monthly schedule. In one variation, the compound is administered everytwo months. In one variation, the compound is administered every threemonths. In one variation, the compound is administered every fourmonths. In one variation, the compound is administered every fivemonths. In one variation, the compound is administered every 6 months.

The dosage or dosing frequency of a compound disclosed herein, or apharmaceutically acceptable salt thereof, may be adjusted over thecourse of the treatment, based on the judgment of the administeringphysician. The compound may be administered to a subject (e.g., a human)in an effective amount. In certain embodiments, the compound isadministered once daily.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of Formula (I), or a pharmaceutically acceptable salt, thereof.When referring to these preformulation compositions as homogeneous, theactive ingredient may be dispersed evenly throughout the composition sothat the composition may be readily subdivided into equally effectiveunit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

In some embodiments, formulations suitable for parenteral administration(e.g., intramuscular (IM) and subcutaneous (SC) administration) willinclude one or more excipients. Excipients should be compatible with theother ingredients of the formulation and physiologically innocuous tothe recipient thereof. Examples of suitable excipients are well known tothe person skilled in the art of parenteral formulation and may be founde.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey &Quinn), 6th edition 2009.

In some embodiments, the compounds described herein, or apharmaceutically acceptable salt thereof, may be administered with asyringe. In some embodiments, the syringe is disposable. In someembodiments, the syringe is reusable. In some embodiments, the syringeis pre-filled with a compound described herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the compounds described herein, or apharmaceutically acceptable salt thereof, may be administered with anauto-injector comprising a syringe. In some embodiments, the syringe isdisposable. In some embodiments, the syringe is reusable. In someembodiments, the syringe is pre-filled with a compound described herein,or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a humanimmunodeficiency virus (HIV) infection comprising administering atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, to a subject in need thereof,is provided. In certain embodiments, a method of treating a humanimmunodeficiency virus (HIV) infection comprising administering atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, to a subject in need thereof,is provided. In certain embodiments, the method comprises administeringa compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one, two, three, or four additionaltherapeutic agents. In certain embodiments, the subject is at risk ofcontracting the HIV virus, such as a subject who has one or more riskfactors known to be associated with contracting the HIV virus. Incertain embodiments, the subject may have not previously receivedantiviral treatment (treatment naïve). In certain embodiments, thesubject may have previously received antiviral treatment (treatmentexperienced). In certain embodiments, the subject may have previouslyreceived antiviral treatment and developed resistance to the previouslyreceived antiviral treatment.

In certain embodiments, a method of treating or preventing a humanimmunodeficiency virus (HIV) infection comprising administering atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, to a subject in need thereof,in combination with a therapeutically effective amount of one or more(e.g., one, two, three, or four; or one or two; or one to three; or oneto four) additional therapeutic agents selected from the groupconsisting of combination drugs for HIV, other drugs for treating HIV,HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitorsof reverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, HIV entry inhibitors, HIVmaturation inhibitors, latency reversing agents, compounds that targetthe HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase(PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C5a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAGprotein inhibitors, HIV POL protein inhibitors, Complement Factor Hmodulators, ubiquitin ligase inhibitors, deoxycytidine kinaseinhibitors, cyclin dependent kinase inhibitors, proprotein convertasePC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reversetranscriptase priming complex inhibitors, G6PD and NADH-oxidaseinhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIVvaccines, or any combinations thereof, is provided. In certainembodiments, the one or more (e.g., one, two, three, or four; or one ortwo; or one to three; or one to four) additional therapeutic agents areselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or any combinations thereof. In certain embodiments, the one or moreadditional therapeutic agent does not include a pharmacokineticenhancer.

In certain embodiments, a method for inhibiting the replication of theHIV virus, treating AIDS or delaying the onset of AIDS in a subject(e.g., a human), comprising administering a compound disclosed herein,or a pharmaceutically acceptable salt thereof, to the subject isdisclosed.

In certain embodiments, a compound of disclosed herein, or apharmaceutically acceptable salt thereof for use in medical therapy ofan HIV infection (e.g. HIV-1 or the replication of the HIV virus (e.g.HIV-1) or AIDS or delaying the onset of AIDS in a subject (e.g., ahuman)) is disclosed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating an HIV infection or the replication of the HIVvirus or AIDS or delaying the onset of AIDS in a subject (e.g., a human)is disclosed. One embodiment relates to a compound disclosed herein, ora pharmaceutically acceptable salt thereof, for use in the prophylacticor therapeutic treatment of an HIV infection or AIDS or for use in thetherapeutic treatment or delaying the onset of AIDS.

In certain embodiments, the use of a compound disclsed herein, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for an HIV infection in a subject (e.g., a human) isdisclosed. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment of an HIV infection is disclosed.

In certain embodiments, in the methods of use, the administration is toa subject (e.g., a human) in need of the treatment. In certainembodiments, in the methods of use, the administration is to a subject(e.g., a human) who is at risk of developing AIDS.

The compounds disclosed herein, or a pharmaceutically acceptable saltthereof, for use in therapy is provided. In one embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, is foruse in a method of treating an HIV infection or the replication of theHIV virus or AIDS or delaying the onset of AIDS in a subject (e.g., ahuman).

The compounds disclosed herein, or a pharmaceutically acceptable saltthereof, for use in a method of treating or preventing HIV infection ina subject in need thereof is provided. In certain embodiments, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, for use in a method of treating HIV infection in a subject inneed thereof is provided. In certain embodiments, the subject in needthereof is a human who has been infected with HIV. In certainembodiments, the subject in need thereof is a human who has beeninfected with HIV but who has not developed AIDS. In certainembodiments, the subject in need thereof is a subject at risk fordeveloping AIDS. In certain embodiments, the subject in need thereof isa human who has been infected with HIV and who has developed AIDS.

In one embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with one or more (e.g. one, two,three, or four; or one or two; or one to three; or one to four)additional therapeutic agents as described herein for use in a method oftreating or preventing HIV infection in a subject in need thereof isprovided. In one embodiment, said additional therapeutic agents areselected from the group consisting of combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or any combinationsthereof. In certain embodiments, said additional therapeutic agents areselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or any combinations thereof.

In one embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a first additionaltherapeutic agent selected from the group consisting of tenofoviralafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine, is provided foruse in a method of treating or preventing HIV infection in a subject inneed thereof. In a particular embodiment, a compound disclosed herein,or a pharmaceutically acceptable salt thereof, in combination with afirst additional therapeutic agent selected from the group consisting oftenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovirdisoproxil hemifumarate, and a second additional therapeutic agent,wherein the second additional therapeutic agent is emtricitabine, isprovided for use in a method of treating or preventing HIV infection ina subject in need thereof.

In a particular embodiment, a compound disclosed herein or apharmaceutically acceptable salt thereof, are provided for use toprevent HIV infection from taking hold if the individual is exposed tothe virus and/or to keep the virus from establishing a permanentinfection and/or to prevent the appearance of symptoms of the diseaseand/or to prevent the virus from reaching detectable levels in theblood, for example for pre-exposure prophylaxis (PrEP) or post-exposureprophylaxis (PEP). Accordingly, in certain embodiments, methods forreducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) areprovided. For example, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a compounddisclosed herein, or a pharmaceutically acceptable salt thereof. Incertain embodiments, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more additional therapeutic agents. In certainembodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1and/or HIV-2) comprise administration of a pharmaceutical compositioncomprising a therapeutically effective amount of the compound disclosedherein, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In certain embodiments, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a compound ofdisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with safer sex practices. In certain embodiments, methodsfor reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2)comprise administration to an individual at risk of acquiring HIV.Examples of individuals at high risk for acquiring HIV include, withoutlimitation, an individual who is at risk of sexual transmission of HIV.

In certain embodiments, the reduction in risk of acquiring HIV is atleast about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certainembodiments, the reduction in risk of acquiring HIV is at least about75%. In certain embodiments, the reduction in risk of acquiring HIV isabout 80%, 85%, or 90%.

In another embodiment, the use of a compound disclosed herein, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of an HIV infection in a human being havingor at risk of having the infection is disclosed.

Also disclosed herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in the therapeutictreatment or delaying the onset of AIDS.

Also disclosed herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment of an HIV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof can be used as a research tool(e.g. to study the inhibition of HIV reverse transcriptase in a subjector in vitro).

Kits that include a compound of Formula (I), or a pharmaceuticallyacceptable salt, thereof, and suitable packaging are provided. In oneembodiment, a kit further includes instructions for use. In one aspect,a kit includes a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and instructions for use of the compounds inthe treatment of the diseases or conditions described herein.

Articles of manufacture that include a compound of Formula (I), or apharmaceutically acceptable salt thereof, in a suitable container areprovided. The container may be a vial, jar, ampoule, preloaded syringe,and intravenous bag.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and the one or more additional therapeutic agents are bothpresent in the body of the patient. When administered sequentially, thecombination may be administered in two or more administrations.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. For example, thecompound disclosed herein may be administered within seconds, minutes,or hours of the administration of the one or more additional therapeuticagents. In some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, a unit dose of one or more additional therapeuticagents is administered first, followed by administration of a unit doseof a compound disclosed herein within seconds or minutes. In otherembodiments, a unit dose of a compound disclosed herein is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of one or more additional therapeuticagents. In yet other embodiments, a unit dose of one or more additionaltherapeutic agents is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of a compounddisclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, pharmacokinetic enhancers, and combinations thereof.

In some embodiments, a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as compounds that target theHIV capsid, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In some embodiments, the compounds that target the HIV capsid areselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromimmunomodulators, immunotherapeutic agents, antibody-drug conjugates,gene modifiers, gene editors (such as CRISPR/Cas9, zinc fingernucleases, homing nucleases, synthetic nucleases, TALENs), and celltherapies such as chimeric antigen receptor T-cell, CAR-T (e.g.,YESCARTA® (axicabtagene ciloleucel)), and engineered T cell receptors,TCR-T.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); darunavir, tenofovir alafenamidehemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, andtenofovir disoproxil fumarate; lamivudine and tenofovir disoproxilfumarate; tenofovir and lamivudine; tenofovir alafenamide andemtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine;tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine;tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, andelvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®;lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, andlamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine;ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate andcobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat;dolutegravir and rilpivirine; dolutegravir and rilpivirinehydrochloride; dolutegravir, abacavir sulfate, and lamivudine;lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine;doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine,lamivudine, and tenofovir disoproxil; dolutegravir+lamivudine,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine, lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, and tenofovir disoproxilfumarate +emtricitabine+rilpivirine hydrochloride, lopinavir, ritonavir,zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, H1 viral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-sh1-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205,PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452,TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,AIC-292, KM-023, and VM-1500.

In some embodiments, examples of HIV non-nucleoside or non-nucleotideinhibitors of reverse transcriptase include dapivirine, delavirdine,delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan,nevirapine, rilpivirine, AIC-292, KM-023, PC-1005, and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, andKP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives,integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217,NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173,NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptideC25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA,SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamicacid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitorssuch as largazole analogs, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621,AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series;

In some embodiments, examples of capsid inhibitors include:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the capsid inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the capsid inhibitor is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the capsid inhibitor is:

or a pharmaceutically acceptable salt thereof.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9,tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein,normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinantinterleukin-15, RPI-MN, GS-9620, and IR-103.

In some embodiments, examples of immune-based therapies includetoll-like receptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5,tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed celldeath protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1)modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil(hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa;interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa;interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its esterderivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein,normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinantinterleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators,NOD2 modulators, and IR-103.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, 1NCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

alpha-4/beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies , anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecificantibodies, anti-nef single domain antibodies, anti-Rev antibody,camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIVtherapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab,Immuglo, MB-66

Examples of those targeting HIV in such a manner include bavituximab,UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121,MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523,VRC-HIVMAB080-00-AB, MGD-014 and VRC07.

In some embodiments, examples of those targeting HIV in such a mannerinclude bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10,8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133,MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4,CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB,VRC-HIVMAB060-00-AB, MGD-014 and VRC07. Example of HIV bispecificantibodies include MGD014.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-05, VAC-3S, multiclade DNA recombinant adenovirus-5(rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3NSSP ISA-51, poly-ICLC adjuvanted vaccines,TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4,HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001,ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particlevaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusionvaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine,anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cellvaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIVvaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptidevaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine,recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine,RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIVvaccine , UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptidevaccine, rAdS gag-pol env A/B/C vaccine.

In some embodiments, examples of HIV vaccines include peptide vaccines,recombinant subunit protein vaccines, live vector vaccines, DNAvaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120(AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomericgp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48,DCVax-001 (CDX-2401), Vacc-4x, Vacc-05, VAC-3S, multiclade DNArecombinant adenovirus-5 (rAdS), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNAvaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLCadjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06),gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine,AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1,NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21,TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2,PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR,DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401,rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201,PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, andvirus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac,LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/envDNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine,dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHC class II epitopehybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Envvaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gagvaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIVvaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4,therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variantgp120 polypeptide vaccine, rAdS gag-pol env A/B/C vaccine, DNA.HTI andMVA.HTI.

HIV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, and a second additional therapeutic agentselected from the group consisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with a capsid inhibitor(s) (e.g.,capsid polymerization inhibitors and/or capsid disrupting compounds).

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with (about 10 to about 1000 mg) ofa capsid inhibitor selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with a capsid inhibitor selectedfrom:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with:

or a pharmaceutically acceptable salt thereof.

A compound as disclosed herein (e.g., any compound of Formula (I)) maybe combined with one or more additional therapeutic agents in any dosageamount of the compound of Formula (I) (e.g., from 1 mg to 1000 mg ofcompound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide, in the form of tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide, or anysalt of solvate form of tenofovir alafenamide. In certain embodiments, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-30 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-10, 5-15,5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with10 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 25 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. A compound as disclosed herein (e.g., acompound of formula (I)) may be combined with the agents provided hereinin any dosage amount of the compound (e.g., from 1 mg to 1000 mg ofcompound) the same as if each combination of dosages were specificallyand individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of formula (I)) may be combined with the agentsprovided herein in any dosage amount of the compound (e.g., from 1 mg to1000 mg of compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceuticaly acceptable salt thereof, is combined with a HIVnucleoside or nucleotide inhibitor and an integrase inhibitor. Incertain embodiments, a compound disclosed herein, or a pharmaceuticalyacceptable salt thereof, is combined with GS-9131 and bictegravir.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are provided.

Birth Control (Contraceptive) Combination Therapy

Therapeutic agents used for birth control (contraceptive) includecyproterone acetate, desogestrel, dienogest, drospirenone, estradiolvalerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate,levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol,mifepristone, misoprostol, nomegestrol acetate, norelgestromin,norethindrone, noretynodrel, norgestimate, ormeloxifen, segestersoneacetate, ulipristal acetate, and any combinations thereof.

Gene Therapy and Cell Therapy

Gene Therapy and Cell Therapy including the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Gene Editors

The genome editing system is selected from the group consisting of: aCRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, ahoming endonucleases system, and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT101.

CAR-T Cell Therapy

A population of immune effector cells engineered to express a chimericantigen receptor (CAR), wherein the CAR comprises an HIV antigen-bindingdomain. The HIV antigen include an HIV envelope protein or a portionthereof, gp120 or a portion thereof, a CD4 binding site on gp120, theCD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120,the membrane proximal region on gp41. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+T cell, aCD8+T cell, or a combination thereof.

Examples of HIV CAR-T include VC-CAR-T.

TCR-T Cell Therapy

TCR-T cells are engineered to target HIV derived peptides present on thesurface of virus-infected cells.

Certain embodiments of the methods disclosed herein exclude theadministration of a pharmacokinetic enhancer. For example, in certainmethods disclosed herein, the subject is not administered apharmacokinetic enhancer, such as cobicistat or ritonavir, during thetreatment with a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof. Thus, in certain embodiments, a method oftreating or preventing a human immunodeficiency virus (HIV) infection isprovided, comprising administering a therapeutically effective amount ofa compound disclosed herein, or a pharmaceutically acceptable saltthereof, to a subject in need thereof, wherein the treatment does notcomprise administration of a pharmacokinetic enhancer. In certainembodiments, a method of treating or preventing a human immunodeficiencyvirus (HIV) infection is provided, comprising administering atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, once daily to a subject inneed thereof, wherein the treatment does not comprise administration ofa pharmacokinetic enhancer.

The present disclosure also provides all of the P, S, A and Iintermediates described in the Examples section below.

EXAMPLES

Methods for preparing the novel compounds described herein will beapparent to those of skill in the art with suitable procedures beingdescribed, for example, in the reaction schemes and examples below.

Sections 1.1-1.8 provide exemplary synthetic schemes for assemblingcompounds of Formula I. Sections 2.1-2.4 show preparation ofIntermediate I, Intermediate P, Intermediate S, and Intermediate A, asused herein. Section 3 provides example syntheses and compounds. Section4 shows biological activity.

1. General Schemes

Scheme 1.1 shows a general synthesis of a compound within the scope ofFormula I beginning with reductive amination of compound 1.1a with asubstituted benzaldehyde (Intermediate P). Reductive amination may beaccomplished, for example, with a cyanoborohydride reagent such assodium cyanoborohydride. Subsequent metal-catalyzed coupling such asSonogashira- or Suzuki-couplings. Sonogashira coupling of compound 1.1bwith an alkynyl Intermediate S^(a) gives a compound of Formula I.

Examples 1-130, 219, and 224-245 were prepared by this general strategy(by reductive amination of the appropriate Intermediate P with thecorresponding organohalide peptide Intermediate I, followed bySonogashira coupling with the appropriate Intermediate S). Example 1provides exemplary reaction conditions and reagents appropriate forpreparing a compound of Formula I according to Scheme 1.1.

Scheme 1.2 shows a general synthesis of a compound within the scope ofFormula I with reductive amination of a protected amino hydrazinyliodophenyl butanol, compound 1.2a. Exemplary protecting groups (PG) forcompound 1.2a include t-butylcarbonyl (BOC) protecting group andfluuorenylmethyloxycarbonyl (FMOC). Reductive amination of compound 1.2awith a substituted benzaldehyde Intermediate P gives compound 1.2b afterremoval of the protecting groups. Reductive amination may beaccomplished, by way of non-limiting example, with sodiumcyanoborohydride. HATU coupling of compound 1.2b with an amino acidIntermediate A^(m) gives a compound 1.2c. Sonogashira coupling ofcompound 1.2c with an alkyne Intermediate S^(a) gives a compound ofFormula I.

Examples 133-180 and 220 were prepared by this general strategy(reductive amination of the appropriate P with an amino hydrazinyliodophenyl butanol followed by HATU coupling A^(m), which is thenfollowed by Sonogashira coupling with an alkynyl Intermediate S^(a)).Example 133 provides exemplary reaction conditions and reagentsappropriate for preparing a compound of Formula I according to Scheme1.2.

Scheme 1.3 shows a general synthesis of a compound within the scope ofFormula I beginning with reductive amination of a protected organohalidecompound 1.3a with a benzaldehyde Intermediate P and Boc removal to givecompound 1.3b. Reductive amination may be accomplished, by way ofnon-limiting example, with sodium cyanoborohydride. Boc removal may beaccomplished, by way of non-limiting examples, with trifluoroacetic acidor hydrochloric acid. HATU coupling of compound 1.3b with an amino acidIntermediate A^(m) gives the intermediate peptide 1.3c. Sonogashiracoupling of the intermediate peptide 1.3c and an alkynyl Intermediate Sgives intermediate 1.3d. Subsequent reaction of compound 1.3d with anacyl chloride gives a compound of Formula I.

Examples 183-186 were prepared by this general strategy. Example 183provides exemplary reaction conditions and reagents appropriate forpreparing a compound of the invention according to Scheme 1.3.

X¹ may be installed directly on the halophenyl as exemplified in Scheme1.4. In this example, an organohalide Intermediate S^(L) (shown abovewhere L is iodo, bromo, or chloro) is coupled with compound 1.4a byBorylation-Suzuki reaction. Examples 188-201 were prepared using themethodology shown in Scheme 1.4. Exemplary reaction conditions are foundin Example 188.

Alternatively, X¹ may be installed by metal catalyzed coupling of aboronic acid or boronic ester (Intermediate S^(b)) with compound 1.5a.The reaction is conducted with XPhos Pd G₂. Xphos is also known as XPhosis 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. Pd G₂ ischloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).Examples 202-211 and 218 were prepared according to Scheme 1.5. Example202 provides exemplary reaction conditions for this transformation.

Example 212 was made in according to Scheme 1.6. Example 212 providesexemplary reaction conditions for transformations according to Scheme1.6.

Scheme 1.7 shows an example of a Suzuki cross coupling, followed byBoc-deprotection and amide bond formation. Exemplary reaction conditionscan be found in Example 213. Examples 214-217 show installation ofdifferent R² and R³ groups using the same general strategy and theappropriate acid chloride.

Scheme 1.8 shows a general synthesis of a compound within the scope ofFormula I beginning with reductive amination of compound 1.8a with asubstituted benzaldehyde (Intermediate P). Reductive amination ofcompound 1.8a with a substituted benzaldehyde Intermediate P givescompound 1.8b. Reductive amination may be accomplished, by way ofnon-limiting example, with sodium cyanoborohydride. Subsequent epoxideopening of tert-butyl((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate give compound1.8c. Subsequent Boc removal followed by Subsequent amide bond formationgives compound 1.8d. Boc removal may be accomplished, by way ofnon-limiting examples, with trifluoroacetic acid or hydrochloric acid.Amide bond formation may be accomplished, by way of non-limitingexample, with a carboxylic acid and a reagent, such as HATU. Subsequentprotecting group removal gives compound 1.8e. Subsequent amide bondformation gives compound 1.8f. Amide bond formation may be accomplished,by way of non-limiting example, with a carboxylic acid and a reagent,such as HATU. Subsequently metal-catalyzed coupling such as Sonogashira-or Suzuki-couplings may be peformed. Sonogashira coupling of compound1.8d with an alkynyl Intermediate S^(a) gives a compound of Formula I.

Examples 221-223 were prepared by this general strategy.

2. Synthesis of Intermediates

2.1 Synthesis of P Intermediates

4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzaldehyde (P1). Asuspension of 4-bromo-1H-imidazole (1 g, 6.8 mmol) cesium carbonate(44430 mg, 136.36 mmol), and difluoroiodomethane (10% wt. in THF, 20 ml,10.62 mmol) in a 75 mL sealed vessel was heated at 50° C. overnight. Thereaction mixture was cooled to room temperature and then filteredthrough Celite. The filter cake was washed with EtOAc. The filtrate waswashed with brine, dried over sodium sulfate and carefully concentrated.The residue was purified by silica column chromatography (17% to 47%EtOAc/Hex) to give 1.3 g of a mixture of regioisomers. This mixture wascombined with 3,5-Difluoro-4-formylphenylboronic acid (1.6 g, 8.58mmol), XPhos Pd G2 (0.4 g, 0.26 mmol),2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.12 g, 0.26mmol), Potassium phosphate tribasic (2 M, 3.3 ml) in dioxane (11 ml) anddegassed for 10 min with argon, then heated at 100° C. overnight. Thereaction mixture was cooled to room temperature, concentrated underreduce pressure, the residue was diluted with EtOAc and washed withbrine 2× then dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(23% to 92% EtOAc/Hex) to give the desired isomer P1. MS (ESI) m/z 259.2[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.32 (d, J=1.1 Hz, 1H), 7.91(d, J=1.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.48-7.36 (m, 2H), 7.16 (t,J=60.8 Hz, 1H).

4-(1-(difluoromethyl)-1H-imidazol-4-yl)benzaldehyde (P2). The titlecompound P2 was prepared according to the method presented for thesynthesis of intermediate P1 but instead utilizing(4-formylphenyl)boronic acid. MS (ESI) m/z 223.2 [M+H]^(|). ¹H NMR (400MHz, Chloroform-d) δ 10.02 (s, 1H), 8.01-7.89 (m, 5H), 7.62 (d, J=1.3Hz, 1H), 7.15 (t, J=60.9 Hz, 1H).

4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzaldehyde (P3).To a heterogeneous solution of Cupric bromide (3.8 g, 17 mmol) andtert-Butyl nitrite (2.53 ml, 21.25 mmol) in MeCN (78 mL) in a 3 neckflask charged with a stir bar, side arm inlet, under argon, was added5-cyclopropyl-1,3,4-thiadiazol-2-amine (2 g, 14.16 mmol) slowly due toexothermic reaction, and stirred at room temperature under argonovernight. The reaction mixture was quenched with 78 mL of saturatedNH4Cl (aq) and extracted with diethyl ether and the organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica column chromatography (10% to 50% EtOAc/Hex). Theproduct (0.28 g, 1.34 mmol) was combined with3,5-Difluoro-4-formylphenylboronic acid (0.5 g, 2.69 mmol), XPhos Pd G2(0.15 g, 0.09 mmol),2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (45.06 mg, 0.09mmol), potassium phosphate tribasic (2 M, 1.34 ml) in dioxane (4.9 ml)and degassed for 10 min with argon, then heated at 100° C. overnight.The reaction mixture was cooled to room temperature, concentrated underreduce pressure, the residue was diluted with EtOAc and washed withbrine 2× then dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(21% to 100% EtOAc/Hex) to give the desired isomer P3. MS (ESI) m/z267.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1H), 7.56 (d,J=9.0 Hz, 2H), 5.30 (d, J=0.7 Hz, 0H), 2.47 (dt, J=8.1, 3.7 Hz, 1H),1.55 (s, 5H), 1.33 (dd, J=8.3, 4.1 Hz, 2H), 1.26 (d, J=4.4 Hz, 5H),0.92-0.79 (m, 2H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P4) In a 150 mL pressure vessel, a suspension of3-bromo-1H-pyrazole (8 g, 54.43 mmol) cesium carbonate (53.2 g, 163.29mmol), and difluoroiodomethane (10% wt. in THF, 200 ml, 106.23 mmol) washeated at 45° C. overnight. The reaction mixture was cooled to roomtemperature and then filtered through Celite. The filter cake was washedwith Et₂O (3×150 mL). The filtrate was washed with brine, dried oversodium sulfate and carefully concentrated (20° C. bath, 100 mb vacuum)to give ˜17 g of a 1.5:1 ratio of regioisomers and solvent stillpresent. This crude material was combined with3,5-Difluoro-4-formylphenylboronic acid (12.65 g, 68.03 mmol), Palladiumacetate (0.31 g, 1.381 mmol), butyldi-1-adamantylphosphine (1.171 g,3.265 mmol) and Potassium carbonate (22.80 g, 164.96 mmol) in dioxane(150 mL) and water (50 mL) the mixture was degassed for 10 min withargon, then heated at 100° C. overnight. The reaction mixture was cooledto room temperature, concentrated under reduce pressure, the residue wasdiluted with EtOAc and washed with brine 2× then dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (5% to 15% EtOAc/Hex). Mixedfractions were recrystallized (5:1 Hex/EtOAc) combined pure productafforded P4. ¹H NMR (400 MHz, Chloroform-d) δ 10.35 (d, J=1.0 Hz, 1H),7.92 (d, J=2.8 Hz, 1H), 7.46 (d, J=9.6 Hz, 2H), 7.24 (t, J=60.5 Hz, 1H),6.80 (d, J=2.8 Hz, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde(P5). The title compound P5 was prepared according to the methodpresented for the synthesis of intermediate P4 but instead utilizing(3-fluoro-4-formylphenyl)boronic acid. ¹H NMR (400 MHz, Chloroform-d) δ10.41 (s, 1H), 7.97 (dd, J=8.0, 7.1 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H),7.50-7.34 (m, 2H), 6.55 (d, J=1.7 Hz, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzaldehyde (P6).The title compound P6 was prepared according to the method presented forthe synthesis of intermediate P4 but instead utilizing(4-formylphenyl)boronic acid. ¹H NMR (400 MHz, Chloroform-d) δ 10.05 (s,1H), 8.03-7.93 (m, 4H), 7.90 (d, J=2.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H).

Synthesis of4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzaldehyde (P7). Asuspension of1-Difluoromethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(1.47 g, 6.03 mmol), 4-bromo-2,6-difluorobenzaldehyde (1.1 g, 4.98mmol), palladium acetate (0.03 g, 0.12 mmol),butyldi-1-adamantylphosphine (0.11 g, 0.3 mmol), and potassium carbonate(2.06 g, 14.93 mmol) in water (7 ml) and 1,4-dioxane (22 ml) in a tubewas degassed for 10 min with argon, then the tube was sealed and heatedat 100° C. overnight. The reaction mixture was cooled to roomtemperature, concentrated under reduce pressure, the residue was dilutedwith EtOAc and washed with brine 2× then dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (10% to 25% EtOAc/Hex) to afford P7. ¹H NMR(400 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H),7.23 (t, J=60.4 Hz, 1H), 7.14 (d, J=9.5 Hz, 2H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzaldehyde(P8). The title compound P8 was prepared according to the methodpresented for the synthesis of intermediate P7 but instead utilizing4-bromo-2-fluorobenzaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.35 (d,J=0.7 Hz, 1H), 8.15 (d, J=0.7 Hz, 1H), 7.98 (q, J=0.8 Hz, 1H), 7.91 (dd,J=8.1, 7.3 Hz, 1H), 7.42 (ddd, J=8.1, 1.7, 0.8 Hz, 1H), 7.31 (dd,J=11.3, 1.6 Hz, 1H), 7.23 (s, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzaldehyde (P9).The title compound P9 was prepared according to the method presented forthe synthesis of intermediate P7 but instead utilizing4-bromobenzaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1H),8.16 (s, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.71-7.66 (m,2H), 7.24 (t, J=0.14 Hz, 1H).

Synthesis of 3-bromo-1-(2,2-difluoroethyl)-1H-pyrazole (P10a) To asolution of 3-bromo-1H-pyrazole (6 g, 42.86 mmol) and Potassiumcarbonate (20.73 g, 150.03 mmol) in DMF (20 mL) at 35° C., was added asolution of 1,1-difluoro-2-iodoethane (24.68 g, 128.59 mmol) dropwisevia an addition funnel. The reaction was stirred overnight then cooledto room temperature, diluted with ether/hexanes and washed with brineand NH₄Cl solution. The organic layer was separated dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (7% to 25% EtOAc/Hex) to affordP10a (5.4 g 63.6%). MS (ESI) m/z 211.0 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.36 (d, J=2.4 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.06(tt, J=55.4, 4.3 Hz, 1H), 4.41 (td, J=13.3, 4.3 Hz, 2H).

Synthesis of4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P10)P10a (4.31 g, 0.02 mol) was combined with3,5-Difluoro-4-formylphenylboronic acid (4.96 g, 24.49 mmol),PdCl₂(tBu₂PPh)₂ (570 mg, 0.92 mmol), and potassium phosphate tribasicmonohydrate (1.0 M, 40.82 ml) in 2-methyltetrahydrofuran (20 mL) andwater (20 mL) the mixture was degassed for 10 min with argon, thenheated at 75° C. overnight. The reaction was cooled to room temperature,the organic layer was separated and the aqueous layer was extracted intoEtOAc. The combined organic layers were washed with 1M HCl, then brine,filter concentrated under reduce pressure, the residue was diluted withEtOAc and washed with brine 2× then dried over Na₂SO₄, filtered andconcentrated under reduced pressure, recrystallized (1:3 EtOAc/hexanes).The separated solids contained a mixture of desired isomer and unreactedboronic acid. This mixture was purified by silica column chromatography(70% to 100% DCM/Hex) to afford P10 (2.3 g, 41%) MS (ESI) m/z 273.1[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.34 (d, J=1.0 Hz, 1H), 7.55(d, J=2.4 Hz, 1H), 7.47-7.38 (m, 2H), 6.67 (d, J=2.4 Hz, 1H), 6.15 (tt,J=55.3, 4.3 Hz, 1H), 4.52 (td, J=13.5, 4.3 Hz, 2H).

Synthesis of4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (P11).The title compound P11 was prepared according to the method presentedfor the synthesis of intermediate P10 but instead utilizing(3-fluoro-4-formylphenyl)boronic acid. ¹H NMR (400 MHz, Chloroform-d) δ10.34 (d, J=0.8 Hz, 1H), 7.89 (dd, J=8.1, 7.2 Hz, 1H), 7.70-7.58 (m,2H), 7.54 (d, J=2.4 Hz, 1H), 7.33 (dt, J=8.0, 1.0 Hz, 0H), 7.26 (dd,J=10.7, 1.5 Hz, 0H), 6.68 (d, J=2.4 Hz, 1H), 6.42 (d, J=1.9 Hz, 0H),6.15 (tt, J=55.4, 4.3 Hz, 1H), 4.52 (td, J=13.5, 4.3 Hz, 2H).

Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzaldehyde(P12). The title compound P12 was prepared according to the methodpresented for the synthesis of compound P10 but instead utilizing(4-formylphenyl)boronic acid. MS (ESI) m/z 273.1 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 10.34 (d, J=1.0 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H),7.47-7.38 (m, 2H), 6.67 (d, J=2.4 Hz, 1H), 6.15 (tt, J=55.3, 4.3 Hz,1H), 4.52 (td, J=13.5, 4.3 Hz, 2H).

Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde(P13) A suspension of copper(II) acetate anhydrous (3.7 g, 20.41 mmol),and 2,2′-bipyridyl (3.2 g, 20.41 mmol) in DCE (40 mL) was degassed,warmed to 50° C., and stirred for 10 minutes, before addition to3-bromo-1H-Pyrazole (3 g, 20.41 mmol), cyclopropylboronic acid (5.3 g,20.41) and sodium carbonate (4.8 g, 44.91 mmol) in DCE (60 mL). Thereaction was stirred at 65° C. for 48 h. The reaction mixture was coolto room temperature, filtered through a Celite frit, and rinsed withEtOAc. The filtrate was concentrated under reduced pressure, the residuewas partitioned between EtOAc and NH₄Cl solution, the organic layer waswashed with NH₄Cl, Na₂CO₃ soln. brine, dried over Na₂SO₄ and purified bysilica column chromatography (10% to 35% EtOAc/Hex) to afford3-bromo-1-cyclopropyl-1H-pyrazole . 3-bromo-1-cyclopropyl-1H-pyrazole(1.5 g, 8.18 mmol) was combined with 3,5-Difluoro-4-formylphenylboronicacid (1.8 g, 9.8 mmol), PdCl₂(tBu₂PPh)₂ (0.29 g, 0.41 mmol), andpotassium phosphate tribasic monohydrate (4.71 g, 20.45 mmol) in2-methyltetrahydrofuran (60 mL) and water (60 mL) was degassed for 10min with argon, then heated to reflux for 3 h. The reaction mixture wascooled to room temperature, the organic layer was separated and theaqueous layer was extracted into EtOAc. The combined organic layers werewashed with 1M HCl, then brine, filtered and concentrated under reducepressure, the residue was diluted with EtOAc and washed with brine 2×then dried over Na₂SO₄, filtered and concentrated under reducedpressure. This mixture was purified by silica column chromatography (50%to 100% DCM/Hex-10% EtOAc/DCM) to afford P13 (1.2 g, 49%) MS (ESI) m/z249.2 [M+H]^(|). ¹H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 7.52(d, J=2.4 Hz, 1H), 7.42 (d, J=10.1 Hz, 2H), 6.57 (d, J=2.4 Hz, 1H), 3.66(tt, J=7.4, 3.9 Hz, 1H), 1.26-1.15 (m, 2H), 1.09 (qd, J=5.7, 2.4 Hz,2H).

Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P14). Asuspension of 2-bromo-5-fluoropyridine (0.95 g, 5.39 mmol),3,5-Difluoro-4-formylphenylboronic acid (0.8 g, 4.3 mmol),bis(triphenylphosphine) palladium (II) dichloride (302 mg, 0.43 mmol),and potassium carbonate (1.49 g, 10.76 mmol) in a mixture of DME (10 ml)and water (5 ml) was degassed for 10 min with argon, then heated at 85°C. overnight. The reaction mixture was cooled to room temperature,concentrated under reduce pressure, the residue was diluted with EtOAcand washed with brine 2× then dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (10% to 20% EtOAc/Hex) to afford P14 (122mg, 12%). MS (ESI) m/z 238.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ10.38 (d, J=1.2 Hz, 1H), 8.59 (d, J=2.8 Hz, 1H), 7.78 (ddd, J=8.8, 4.2,0.6 Hz, 1H), 7.68-7.60 (m, 2H), 7.55 (ddd, J=8.8, 7.8, 2.9 Hz, 1H).

Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P15).The title compound P15 was prepared according to the method presentedfor the synthesis of compound P14 but instead utilizing2-bromo-4-fluoropyridine. MS (ESI) m/z 238.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 10.39 (s, 1H), 8.70 (dd, J=8.6, 5.5 Hz, 1H), 7.67 (d,J=9.9 Hz, 3H), 7.48 (dd, J=9.8, 2.3 Hz, 1H), 7.11 (ddd, J=7.9, 5.5, 2.3Hz, 1H).

Synthesis of 2,6-difluoro-4-(pyrimidin-2-yl)benzaldehyde (P16).2-bromopyrimidine (1 g, 6.29 mmol) andtetrakis(triphenylphosphine)palladium (218.05 mg, 0.19 mmol) in1,2-dimethoxyethane (30 ml) were degassed for 5 min, then Water (15 ml)was added followed by 3,5-difluoro-4-formylphenylboronic acid (1.4 g,7.55 mmol) and sodium bicarbonate (1.0M in THF, 1.59 g, 18.87 mmol). Thereaction mixture was heated at 85° C. overnight. After cooling to roomtemperature, the mixture was diluted with EtOAc and washed with sat.NaHCO₃ solution and brine then dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (0% to 40% EtOAc/Hex to afford P16. ¹H NMR(400 MHz, Chloroform-d) δ 10.42 (d, J=1.0 Hz, 1H), 8.87 (d, J=4.9 Hz,2H), 8.16-8.03 (m, 2H), 7.32 (t, J=4.8 Hz, 1H).

(S)-2,6-difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde(P17) To a solution of 3-bromo-1H-pyrazole (583 mg, 3.97 mmol) in DMF(15 mL) cooled in an ice bath was added sodium hydride (60% oildispersion, 241 mg, 6.03 mmol). After stirring for 1.5 h, a solution of(R)-tetrahydrofuran-3-yl methanesulfonate (Reference: PCT Int Appl2013068458) (998 mg, 6.01 mmol) in DMF (5 mL) was added and the reactionmixture was heated to 100° C. overnight. The reaction mixture was cooledto room temperature, diluted with EtOAc and washed with brine. Theorganic layer was separated, dried over Na₂SO₄, concentrated undervacuum and the crude residue was purified by silica columnchromatography (20% to 40% EtOAc/Hex to afford(S)-3-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole (0.17 g, 0.78 mmol),this material was combined in a 20 mL microwave vial with3,5-Difluoro-4-formylphenylboronic acid (0.19 g, 1 mmol), palladiumacetate (6.5 mg, 0.03 mmol), butyldi-1-adamantylphosphine (21.4 mg, 0.06mmol), and potassium carbonate (0.33 g, 2.4 mmol) in a mixture of water(2 ml) and 1,4-dioxane (6 ml), the mixture was degassed with argon for 5min. The reaction was microwaved at 100° C. for 1.5 h, then cooled toroom temperature, concentrated under vacuum, then diluted with EtOAc andwashed with water and brine. The organic extract was dried over Na₂SO₄,filtered and concentrated under reduced pressure. This mixture waspurified by silica column chromatography (20% to 40% EtOAc/hex) toafford P17. MS (ESI) m/z 279.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ10.32 (d, J=1.0 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.48-7.34 (m, 2H), 6.62(d, J=2.4 Hz, 1H), 5.03 (ddt, J=8.2, 5.8, 3.4 Hz, 1H), 4.31-4.03 (m,4H), 3.98 (td, J=8.6, 5.5 Hz, 1H), 2.51 (dtd, J=13.4, 8.3, 7.1 Hz, 1H),2.43-2.28 (m, 1H).

(R)-2,6-difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde(P18). The title compound P18 was prepared according to the methodpresented for the synthesis of compound P17 but instead utilizing(S)-tetrahydrofuran-3-yl methanesulfonate (Reference: PCT Int Appl2013068458). MS (ESI) m/z 279.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ10.34 (d, J=1.1 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.50-7.33 (m, 2H), 6.63(d, J=2.4 Hz, 1H), 5.04 (ddt, J=9.0, 6.6, 3.5 Hz, 1H), 4.27-4.04 (m,4H), 3.99 (td, J=8.6, 5.5 Hz, 1H), 2.52 (dtd, J=13.3, 8.2, 7.1 Hz, 1H),2.38 (dddd, J=13.3, 8.0, 5.5, 3.4 Hz, 1H).

2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzaldehyde(P19) The title compound P19 was prepared according to the methodpresented for the synthesis of compound P4 but instead utilizing1-chloro-2-methylpropan-2-ol. MS (ESI) m/z 281.0 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 10.33 (s, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.47-7.35(m, 2H), 6.64 (d, J=2.4 Hz, 1H), 4.13 (s, 2H), 1.22 (s, 7H).

Synthesis of2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzaldehyde(P20). A suspension of S7a (0.14 g, 3.7 mol),(3,5-difluoro-4-formylphenyl)boronic acid (110.29 mg, 5.9 mol),potassium carbonate (0.15 g, 1 mmol), andtetrakis(triphenylphosphine)palladium (20 mg, 0.19 mmol) in a mixture ofdioxane (15 ml) and water (15 ml) was degassed for 10 min. The reactionmixture was heated at 85° C. for 3 h. After cooling to room temperature,the mixture was diluted with EtOAc and washed with sat. NaHCO₃ solutionand brine then dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (0% to 40% EtOAc/Hex to afford P20 (99 mg, 62%). MS (ESI)m/z 387.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.55(s, 1H), 7.11 (d, J=9.8 Hz, 1H), 4.74 (t, J=6.3 Hz, 1H), 4.61 (s, 1H),4.40 (d, J=12.8 Hz, 1H), 3.69 (s, 1H), 3.33-3.02 (m, 3H), 1.86 (s, 1H),1.65 (d, J=8.1 Hz, 1H), 1.55 (s, 2H).

Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)benzaldehyde (P21). Thetitle compound P21was prepared according to the method presented for thesynthesis of compound P13 but instead utilizing (4-formylphenyl)boronicacid. MS (ESI) m/z 213.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.01(s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.92-7.86 (m, 2H), 7.50 (d, J=2.3 Hz,1H), 6.61 (d, J=2.3 Hz, 1H), 3.66 (tt, J=7.4, 3.8 Hz, 1H), 1.22-1.15 (m,2H), 1.11-1.03 (m, 2H).

Synthesis of2,6-difluoro-4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzaldehyde(P22) A suspension of S4a (0.53 g, 1 mmol), by(3,5-difluoro-4-formylphenyl)boronic acid (413.8 mg, 2.0 mmol), andpotassium carbonate (0.16 g, 4 mmol), and Cl₂Pd(tBu₂PPh)₂ (0.02 g, 0.37mmol) in a mixture of dioxane (15 ml) and water (15 ml) were degassedfor 10 min. The reaction mixture was heated at 60° C. for 3 h. Aftercooling to room temperature, the mixture was diluted with EtOAc andwashed with sat. NaHCO₃ solution and brine then dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (1% to 15% (MeOH/(1% E₃N inEtOAc) to afford P22 (470 mg, 85%). MS (ESI) m/z 372.2 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) δ 10.34 (s, 1H), 8.52 (d, J=2.5 Hz, 1H), 7.76(dd, J=8.9, 2.5 Hz, 1H), 7.16 (d, J=10.4 Hz, 2H), 6.61 (d, J=8.8 Hz,1H), 4.71 (t, J=6.2 Hz, 2H), 4.50 (s, 2H), 3.87 (t, J=6.2 Hz, 3H), 3.57(s, 4H), 2.78 (d, J=7.3 Hz, 1H), 1.64 (d, J=8.9 Hz, 1H).

Synthesis of2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzaldehyde(P23) The title compound P23 was prepared according to the methodpresented for the synthesis of compound P20 but instead utilizing S3c.MS (ESI) m/z 386.1 [M+H]^(|).

Synthesis of 2,6-dichloro-4-(pyridin-2-yl)benzaldehyde (P24) and2-chloro-4-(pyridin-2-yl)benzaldehyde (P25). In a sealed tube, methyl4-bromo-2,6-dichlorobenzoateboth (3.18 g, 11.2 mmol) and2-(trimethylstannyl)pyridine (1.94 ml, 11.2 mmol) and tetrakis(triphenylphosphine)palladium (647.1 mg, 0.56 mmol) are suspended in DMF (25 mL).The mixture was degased with argon for 10 min heated to 100° C. for 18hours, and then at room temperature. After 48 h the reaction was dilutedwith EtOAc and washed with KF (3 g in 50 mL water) and brine (3×) anddried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (0% to 20%EtOAc/hexanes) to afford methyl 2,6-dichloro-4-(pyridin-2-yl)benzoate(1.5 g, 47.5%). This material was dissolved in THF (25 mL), cooled to 0°C., then lithium aluminum hydride (0.4 g, 10.63 mmol) was added slowly,after the addition was completed, the reaction mixture was warmed upslowly to room temperature and stirred for 1 h, then cooled back to 0°C. added water (500 uL) slowly (vigorous gas evolution), followed byNaOH (2 M, 500 uL) then water (1500 uL). The slurry was stirred at roomtemperature. After 1 h, Na₂SO₄ was added, and then the mixture wasfiltered through Celite. The solid was rinsed with Et₂O (˜200 mL), andthe filtrate was concentrated under reduced pressure, the residue wasdiluted with EtOAc and washed with water then dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue (1.5g, 5.9 mmol) was combined with pyridinium chlorochromate (1.91 g, 8.85mmol) and Celite (700 mg, 7 mmol), DCM (10 mL) was added and thereaction mixture was stirred at room temperature for 48 h. The reactionwas filtered through a Celite frit with a small plug of silica, andrinsed several times with DCM/EtOAc, and then the filtrate was driedover Na₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography to afford P24 (392mg, 26.3%). MS (ESI) m/z 252.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ10.54 (s, 1H), 8.74 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.06 (s, 2H), 7.83(ddd, J=8.0, 7.4, 1.8 Hz, 1H), 7.77 (dt, J=8.0, 1.1 Hz, 1H), 7.36 (ddd,J=7.4, 4.8, 1.2 Hz, 1H) and P25 (195 mg, 15.2%). MS (ESI) m/z 218.1[M+H]^(|). 1H NMR (400 MHz, Chloroform-d) δ 10.52 (d, J=0.8 Hz, 1H),8.74 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 8.17 (dd, J=1.6, 0.5 Hz, 1H),8.07-7.95 (m, 2H), 7.91-7.75 (m, 2H), 7.39-7.29 (m, 1H).

Synthesis 4-bromo-2,6-difluorobenzaldehyde (P26a) To a solution ofmethyl 4-bromo-2-chloro-6-fluorobenzoate (5.6 g, 20.94 mmol) in DCM (100mL) at −78° C., was added dropwise diisobutylaluminum hydride (1.0M intoluene, 60 ml). After 4.5 h the reaction mixture was quenched with MeOH(2.4 mL), then NaOH (6.0 M, 2.4 mL) followed by water (5 mL). Thereaction was stirred for 1 h, and then Na₂SO₄ was added, filtered, andconcentrated under vacuum, the residue (4.96 g, 20.71 mmol) wasdissolved in DCM (100 mL) and cooled to 5° C., then pyridiniumchlorochromate (6.27 g, 0.03 mol) was added and the mixture was stirredovernight, allowing to slowly warm to room temperature. Silica gel (10g) was added, the mixture was filtered through a 1.5 inch plug of silicagel eluting with 5:1 DCM/EtOAc to give P26a (4.67 g, 92%). ¹H NMR (400MHz, Chloroform-d) δ 10.38 (s, 1H), 7.54-7.41 (m, 1H), 7.31 (dd, J=9.7,1.8 Hz, 1H). ¹⁹F NMR (377 MHz, Chloroform-d) δ-113.31 (d, J=9.7 Hz).

Synthesis of 2-chloro-6-fluoro-4-(pyridin-2-yl)benzaldehyde (P26) To asolution of P26a (2.5 g, 10.53 mmol) and Pd(tBu₂PPh)₂Cl₂ (213 mg, 0.34mmol) in methyl tetrahydrofuran (7 mL) at room temperature, was added2-pyridylzinc bromide (0.5M in THF, 28.43 ml). The reaction was degassedwith Ar for 10 min, and then warmed to 60° C. After 3h the mixture wascooled to room temperature, diluted with EtOAc and washed with saturatedsolution of NH₄Cl. The organic extract was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica column chromatography (3%-35% EtOAc in 1:1 DCM/hexane) toafford P26 (1.09 g, 41%) MS (ESI) m/z 236.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 10.49 (d, J=1.1 Hz, 1H), 8.74 (ddd, J=4.8, 1.8, 1.0 Hz,1H), 7.96 (t, J=1.4 Hz, 1H), 7.86 (d, J=1.8 Hz, 0H), 7.85-7.80 (m, 1H),7.78 (q, J=1.1 Hz, 1H), 7.77-7.74 (m, 1H), 7.36 (ddd, J=7.4, 4.8, 1.2Hz, 1H). ¹⁹F NMR (377 MHz, Chloroform-d) δ-114.35 (d, J=11.6 Hz).

Synthesis of4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2,6-difluorobenzaldehyde(P27). 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (1 g, 0.01 mol)in CH₃CN (5 mL) at 15° C. was combined with cuprous bromide (1.24 g,0.01 mol) and Cupric bromide (16.05 mg, 0.07 mmol), then tert-Butylnitrite (1.11 ml, 0.01 mol) was added very slowly and the reaction wasstirred overnight. The mixture was quenched with aqueous NH4Cl, dilutedwith DCM, the layers were splitted, and the organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (7%-40%EtOAc/hexanes), the product (0.59 g, 2.91 mmol) was combined with3,5-Difluoro-4-formylphenylboronic acid (0.81 g, 4.36 mmol),PdCl₂(tBu₂PPh)₂ (0.08 g, 0.12 mmol), and potassium phosphate tribasicmonohydrate (1.67 g, 7.27 mmol) in 2-methyltetrahydrofuran (25 mL) andwater (60 mL) was degassed for 10 min with argon, then heated to refluxfor 3 h. The reaction mixture was cooled to room temperature, dilutedwith EtOAc, washed with water, 5% citric acid solution, and brine. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was crystallized from EtOAc/ether toafford P27 (486 mg, 63%) MS (ESI) m/z 265.1 [M+H]⁺.

Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P28). The titlecompound P28 was prepared according to the method presented for thesynthesis of compound P20 but instead utilizing 2-bromopyridine. MS(ESI) m/z 202.2 [M+H]⁺.

Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P29). The titlecompound P29 was prepared according to the method presented for thesynthesis of compound P20 but instead utilizing 2-bromopyridine and(3-fluoro-4-formylphenyl)boronic acid. MS (ESI) m/z 220.2 [M+H]⁺.

Synthesis of 4-(pyridin-2-yl)benzaldehyde (P30). The title compound P30was prepared according to the method presented for the synthesis ofcompound P20 but instead utilizing 2-bromopyridine and(4-formylphenyl)boronic acid. MS (ESI) m/z 184.1 [M+H]⁺.

Synthesis of bicyclo[2.2.1]heptane-1-carbaldehyde (P31)Bicyclo[2.2.1]heptane-1-carboxylic acid (1000 mg, 0.01 mol) wasdissolved in methyl tetrahydrofurane (3 mL), cooled to 0° C., thenlithium aluminum hydride (0.5 g, 14 mmol) was added slowly, after theaddition was completed, the reaction mixture was warmed up slowly toroom temperature and stirred for 2 h, the mixture was cooled back to 0°C. added water (540 uL) slowly (vigorous gas evolution), followed byNaOH (2 M, 540 uL) then water (1500 uL). The slurry was stirred at roomtemperature. After 1 h Na₂SO₄ was added then the mixture was filteredthrough Celite. The solid was rinsed with DCM (˜200 mL), and thefiltrate was concentrated under reduced pressure. The crude residue (900mg, 7.13 mmol) was dissolved in DCM (10 mL) cooled in an ice bath andcombined with pyridinium chlorochromate (2.61 g, 12.12 mmol) and Celite(700 mg, 7 mmol), the reaction was allowed to war up to room temperatureslowly and stirred for 48 h. The reaction was filtered through a Celitefrit with a small plug of silica, and rinsed several times with DCM, andthen the filtrate was concentrated under reduced pressure at 5° C. toafford P31 (1.7 g, 95%). ¹H NMR (400 MHz, Chloroform-d) δ 9.85 (s, 1H),2.41 (td, J=4.2, 2.1 Hz, 1H), 2.04-1.27 (m, 10H).

Synthesis of 2,6-difluoro-4-(oxetan-3-yl)benzaldehyde (P32) In a sealedtube, 3-Iodo-oxetane (0.24 ml, 3 mmol),(3,5-difluoro-4-formylphenyl)boronic acid (250 mg, 1.34 mmol),4,4′-Di-tert-butyl-2,2′-dipyridyl (18.05 mg, 0.07 mmol) Ni(NO3)2-6H20(19.55 mg, 0.07 mmol) and Potassium carbonate (557.51 mg, 4.03 mmol) in1,4-Dioxane (5 ml) were combined. The mixture was degased with argon for10 min heated to 80° C. for 12 hours, and then cooled to roomtemperature. After 48 h the reaction was diluted with EtOAc and washedwith brine (2×) and dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (10% to 30% EtOAc/hexanes) to afford P32 (49 mg, 18%). 1HNMR (400 MHz, Chloroform-d) δ 10.26 (d, J=1.2 Hz, 1H), 6.99 (d, J=9.5Hz, 2H), 5.04 (dd, J=8.2, 6.3 Hz, 2H), 4.62 (t, J=6.3 Hz, 2H), 4.14 (tt,J=8.2, 6.2 Hz, 1H).

Synthesis of 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzaldehyde (P33)3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (414.48 mg, 1.97mmol), 4-Bromo-2,6-difluorobenzyl alcohol (0.4 g, 2 mmol),tetrakis(triphenylphosphine)palladium (103.63 mg, 0.09 mmol), and sodiumcarbonate (2M, 2.24 mL) in 1,4-dioxane (6 ml) were combined. The mixturewas degased with argon for 10 min heated to 80° C. for 12 hours, andthen cooled to room temperature. The reaction was diluted with EtOAc andwashed with brine (2×) and dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (20% to 50% EtOAc/hexanes), the product (405 mg, 1.79mmol) was dissolved in EtOAc (8 mL), Palladium (10% on C, 38.1 mg, 0.36mmol) was added and the mixture was stirred at room temperature underhydrogen for 18 h. The mixture was filtered through Celite, and rinsedseveral times with EtOAc, the filtrate was concentrated under reducedpressure. The crude residue (450 mg, 1.97 mmol) was dissolved in DCM (10mL) and combined with pyridinium chlorochromate (637.49 mg, 2.96 mmol),the reaction was stirred at room temperature for 48 h. The reaction wasthen filtered through a Celite and rinsed several times with DCM, thefiltrate was concentrated under reduced pressure to afford P33. 1H NMR(400 MHz, Chloroform-d) δ 10.28 (d, J=1.2 Hz, 1H), 6.85 (d, J=10.0 Hz,2H), 4.08 (dt, J=11.5, 3.2 Hz, 2H), 3.60-3.33 (m, 2H), 2.90-2.71 (m,1H), 1.83-1.70 (m, 4H).

Synthesis of 2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde(P34). The title compound P34 was prepared according to the methodpresented for the synthesis of compound P1 but instead utilizing2-bromo-5-methyl-1,3,4-oxadiazole. MS (ESI) m/z 225.1 [M+H]⁺.

Synthesis of 4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzaldehyde (P35). The title compound P35 wasprepared according to the method presented for the synthesis of compoundP1 but instead utilizing 2-bromo-5-(difluoromethyl)pyridine. MS (ESI)m/z 270.1[M+H]⁺.

Synthesis of 2,6-difluoro-4-(pyrazin-2-yl)benzaldehyde (P36). A mixtureof 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), bis (pinacolato)diboron (3.22 g, 12.67 mmol), dichloro1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane(739.04 mg, 0.9 mmol) and potassium acetate (1776.34 mg, 18.1 mmol) in1,4-dioxane (18 mL) were heated to 90° C. for 12 hours. After cooling toroom temperature 2-bromopyrazine (1.64 ml, 18.1 mmol),tetrakis(triphenylphosphine)palladium (1.05 g, 0.9 mmol) and potassiumcarbonate (2 M, 11.31 ml) were added. The mixture was degassed bypulling vacuum and back-filling with Ar (3×), then the reaction washeated to 90° C. for 12 hours, cooled to room temperature, diluted withEtOAc and washed with saturated solution of brine. The organic extractwas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The crude residue was purified by silica column chromatography (0%-100%EtOAc/DCM/) to afford P36 MS (ESI) m/z 221.1 [M+H]⁺.

Synthesis of 4-(5-fluoropyridin-2-yl)benzaldehyde (P37). The titlecompound P37 was prepared according to the method presented for thesynthesis of compound P14 of but instead utilizing(4-formylphenyl)boronic acid. MS (ESI) m/z 202.14 [M+H]+.

Synthesis of 4-ethynyl-2,6-difluorobenzaldehyde (P38). A solution of4-bromo-2,6-difluorobenzaldehyde Reactant 2 (6 g, 27.15 mmol), CuI(517.06 mg, 2.71 mmol) PdCl₂(tBu₂PPh)₂ (955.53 mg, 1.36 mmol)trimethylsilylacetylene (7.67 ml, 54.3 mmol) in a 3:1 mixture of CH₃CN(50 mL)/Et₃N (10 mL) was degassed with Argon for 10 min. The reactionmixture was heated to 70° C. for 18 h. After cooling to room temperaturethe mixture was filtered through silica, the filtrate was concentratedand purified by silica column chromatography (1%-15% EtOAc/Hex) Theproduct was dissolved in MeOH (5 ml) and Potassium carbonate (1876.01mg, 13.57 mmol) were added, the mixture was stirred at room temperature.After 20 min the reaction was concentrated to dryness, then diluted withDCM and washed with brine. The organic extract was dried over Na₂SO₄ togive p38 (2.99 g, 66%). ¹H NMR (400 MHz, Chloroform-d) δ 10.30 (d, J=1.1Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 0.26 (s, 9H).

Synthesis of 2,6-difluoro-4-(5-methylpyridin-2-yl)benzaldehyde (P39).The title compound P39 was prepared according to the method presentedfor the synthesis of compound P16 but instead utilizing2-bromo-5-methylpyridine.

Synthesis of4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzaldehyde (P40).The title compound P40 was prepared according to the method presentedfor the synthesis of compound P1 but instead utilizing2-bromo-5-cyclopropyl-1,3,4-oxadiazole. MS (ESI) m/z 251.1 [M+H]⁺.

Synthesis of 2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (P41)A solution of 3-bromo-1-methyl-1H-pyrazole (0.14 g, 3.7 mol),(3,5-difluoro-4-formylphenyl)boronic acid (9.19 g, 49.43 mmol), sodiumcarbonate (8.72 g, 82.27 mmol), andtetrakis(triphenylphosphine)palladium (1.9 g, 1.64 mmol) in a mixture of1,2-Dimethoxyethane (84 ml) and water (36 ml) was degassed for 10 min.The reaction mixture was heated at 100° C. for 18 h. After cooling toroom temperature, the mixture was diluted concentrated in vacuo thendiluted with EtOAc and washed with brine then dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (20% to 40% EtOAc/Hex to affordP41. MS (ESI) m/z 223.3 [M+H]⁺.

Synthesis of 2,6-difluoro-4-(1H-pyrazol-3-yl)benzaldehyde (P42). Thetitle compound P42 was prepared according to the method presented forthe synthesis of compound P1 but instead utilizing 3-bromo-1H-pyrazole.MS (ESI) m/z 209.1[M+H]⁺.

Synthesis of 2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzaldehyde(P43). To a suspension of NaH (60%, 310.79 mg, 7.77 mmol) in THF (11 mL)was added oxetan-3-ol (0.42 ml, 6.66 mmol) dropwise, the mixture wasstirred for 30 minutes followed by addition of 2-chloro-4-fluoropyridine(0.5 ml, 5.55 mmol). The reaction mixture was stirred overnight, dilutedwith EtOAc and washed with water and brine then dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (30% to 60% EtOAc/Hex) theproduct (849 mg, 4.57 mmol) was combined with(3,5-difluoro-4-formylphenyl)boronic acid (1020.52 mg, 5.49 mmol)potassium carbonate (2M, 5.49 ml) and Pd(dppf)Cl2 (279.29 mg, 0.46 mmol)in DME (23 ml), the mixture was degassed by pulling vacuum andback-filling with Ar (5×) heated to reflux for 3 h. After cooling toroom temperature, the mixture was diluted with EtOAc and washed withwater and brine then dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (30% to 60% EtOAc/Hex) to afford P43 (1.22 g, 80%). MS(ESI) m/z 292.1 [M+H]⁺.

Synthesis of4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzaldehyde(P44). 4-ethynyl-2,6-difluorobenzaldehyde (1.5 g, 9.0 mmol) wasdissolved in THF (10 mL). Copper(I) thiophene-2-carboxylate (115.71 mg,0.9 mmol) was added followed by azidomethyl pivalate (2.1 mL, 13.5 mmol)over 5 minutes. After 15 minutes, complete conversion was observed byLCMS analysis. The reaction was quenched with aqueous NaHCO₃, and theintermediate product was extracted into ethyl acetate, dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude mixture wasslurried in 40 mL 1:1 MeOH:EtOH, and aqueous NaOH solution was added(2M, 9.9 mL, 19.9 mmol). After 30 minutes aqueous NaHCO₃ was added, andthe intermediate product was extracted into ethyl acetate, dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productwas transferred using THF (20 mL) to a 500 mL pressure vessel containingpotassium carbonate (4.4 g, 32 mmol) and a magnetic stir bar. A solutionof difluoroiodomethane (10% in THF, 68 mL, 36 mmol) was added and thevessel was sealed. The mixture was stirred overnight at 50° C.overnight. The crude mixture was filtered, concentrated in vacuo andpurified by flash column chromatography (0→25% EtOAc in 1:1hexanes:DCM). The desired regioisomer was major and was isolated in themiddle fractions. 1H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1H), 8.31(s, 1H), 7.62 (t, J=58.8 Hz, 1H), 7.59-7.51 (m, 2H). 19F NMR (377 MHz,Chloroform-d) δ-95.78 (d, J=58.9 Hz), -113.68 (d, J=9.2 Hz).

Synthesis of 4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzaldehyde(P45). The title compound P45 was prepared according to the methodpresented for the synthesis of compound P16 but instead utilizing5-bromo-2-(difluoromethyl)pyridine. ¹H NMR (400 MHz, Chloroform-d)δ10.40 (s, 1H), 8.94-8.79 (m, 1H), 8.04 (dd, J=8.2, 2.3 Hz, 1H), 7.79(d, J=8.2 Hz, 1H), 7.25 (d, J=9.3 Hz, 2H), 6.70 (t, J=55.2 Hz, 1H). ¹⁹FNMR (377 MHz, Chloroform-d) δ-113.37 (d, J=9.3 Hz), -116.56 (d, J=55.5Hz).

Synthesis of 4-(1-cyclopropyl-1H-pyrazol-4-yl)benzaldehyde (P46). Thetitle compound P46 was prepared according to the method presented forthe synthesis of compound P7 but instead utilizing(4-formylphenyl)boronic acid and 4-bromo-1-cyclopropyl-1H-pyrazole. MS(ESI) m/z 213.2 [M+H]⁺.

Synthesis of 2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzaldehyde (P47).The title compound P47 was prepared according to the method presentedfor the synthesis of compound P16 but instead utilizing5-bromo-2-methylpyrimidine. MS (ESI) m/z 235.2 [M+H]⁺. 1H NMR (400 MHz,Chloroform-d) δ 10.38 (t, J=1.0 Hz, 1H), 8.86 (s, 2H), 7.30-7.14 (m,3H), 2.82 (s, 3H).

2.2 Synthesis of S Intermediates

Synthesis of tert-butyl7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate(S1a). A solution of tert-butyl3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1 g, 4.38 mmol)2-fluoro-5-iodopyridine (1.12 g, 5.04 mmol), and sodium carbonate (0.84g, 7.88 mmol) in 1-Methyl-2-pyrrolidinone (4 ml) was heated at 85° C.overnight. The mixture was cooled to room temperature, diluted withwater and extracted into DCM. The organic extract was dried over Na₂SO₄filtered and concentrated under reduced pressure. The residue waspurified by silica chromatography to yield S1a (1.57 g, 62.3%). MS (ESI)m/z 431.9 [M+H]^(|). ¹H NMR (400 MHz, Chloroform-d) δ 8.30 (dd, J=2.4,0.7 Hz, 1H), 7.66 (dd, J=9.0, 2.3 Hz, 1H), 6.44 (d, J=9.0 Hz, 1H), 4.25(d, J=12.7 Hz, 1H), 4.21-4.00 (m, 3H), 3.97-3.86 (m, 2H), 3.80 (t,J=11.9 Hz, 2H), 3.26 (t, J=15.1 Hz, 2H), 1.48 (s, 9H).

Synthesis of 7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane(S1b). To a solution of S1a (1.57 g, 0.004 mol) in DCM (15 mL) in awater bath at room temperature was added was added HCl (4.0M in dioxane,4.6 mL). The reaction was stirred at room temperature overnight. Thereaction was concentrated to dryness. MS (ESI) m/z 332.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.26 (dd, J=2.2, 0.7 Hz, 1H), 8.22 (ddd, J=9.5,2.2, 1.0 Hz, 1H), 7.27 (d, J=9.7 Hz, 1H), 4.60 (d, J=14.4 Hz, 2H), 4.21(dt, J=13.5, 0.9 Hz, 2H), 4.08 (dt, J=13.3, 2.4 Hz, 2H), 3.88 (d, J=14.6Hz, 2H), 3.81 (s, 2H).

Synthesis of7-(5-iodopyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane(S1c). To S1b (0.62 g, 8.62 mmol) suspended in NMP (6 mL), was addedEt₃N (0.12 ml, 0.8 mmol), oxetan-3-one (0.51 ml, 8.5 mmol), and sodiumcyanoborohydride (2.62 g, 41.72 mmol) was added and the reaction mixturewas stirred for 5 min then more Et₃N (0.18 ml, 0.1 mmol), stirred atroom temperature for 4 h, then warmed up to 30° C. After 2 h thereaction was cooled to room temperature, diluted with EtOAc and washedwith brine. The organic extract was dried over Na₂SO₄ filtered andconcentrated under reduced pressure to afford S1c (0.84 g, 95%). MS(ESI) m/z 388.1 [M+H]⁺.

Synthesis of7-(5-ethynylpyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane(S1) A solution of S1c (0.84 g, 0 mol), CuI (24.73 mg, 0.13 mmol)PdCl₂(tBu₂PPh)₂ (45.7 mg, 0.06 mmol), trimethylsilylacetylene (0.92 ml,0.01 mol), in a 3:1 mixture of CH₃CN (9 mL)/Et₃N (3 mL) was degassedwith Argon for 10 min. The reaction mixture was heated to 40° C. for 90min. The reaction was diluted with EtOAc and washed with NaHCO3 solutionand dried over Na₂SO₄, filtered and concentrated under reduced pressure.The crude residue was dissolved in MeOH (5 ml) and Potassium carbonate(0.45 g, 3.0 mmol) were added, the mixture was stirred at roomtemperature. After 15 min the reaction was concentrated to dryness, thendiluted with DCM and washed with brine. The organic extract was driedover Na₂SO₄ to give S1 (300 mg 48%). MS (ESI) m/z 286.2 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) δ 8.17 (dd, J=2.3, 0.8 Hz, 1H), 7.40 (dd, J=8.9,2.3 Hz, 1H), 6.35 (dd, J=8.9, 0.8 Hz, 1H), 4.55 (t, J=6.2 Hz, 2H), 4.42(t, J=5.9 Hz, 2H), 4.25 (p, J=6.2 Hz, 1H), 3.84 (dt, J=11.3, 2.2 Hz,2H), 3.78 (d, J=12.9 Hz, 2H), 3.71 (dt, J=11.5, 0.9 Hz, 2H), 3.24 (ddd,J=12.9, 4.9, 2.0 Hz, 2H), 2.92 (s, 1H), 2.65-2.52 (m, 2H).

Synthesis of7-(5-ethynylpyridin-2-yl)-9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane.The title compound S2 was prepared according to the method presented forthe synthesis of compound D1 but instead utilizing formaldehyde. MS(ESI) m/z 244.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J=2.3Hz, 1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 4.01 (d,J=11.2 Hz, 2H), 3.91 (d, J=12.9 Hz, 2H), 3.85 (d, J=11.2 Hz, 2H), 3.53(ddd, J=13.0, 4.8, 2.0 Hz, 2H), 3.07 (s, 1H), 2.86-2.75 (m, 2H), 2.62(s, 3H).

Synthesis of tert-butyl3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S3a)The title compound S3a was prepared according to the method presentedfor the synthesis of compound S1a but instead utilizing tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m/z 415.8 [M+H]⁺.¹H NMR (400 MHz, Chloroform-d) δ 8.36-8.26 (m, 1H), 7.65 (dd, J=9.0, 2.4Hz, 1H), 6.40 (d, J=9.0 Hz, 1H), 4.33 (s, 2H), 3.82 (d, J=40.5 Hz, 2H),3.05 (s, 2H), 1.94 (dd, J=8.7, 4.6 Hz, 2H), 1.73 (d, J=7.3 Hz, 2H), 1.47(s, 9H).

Synthesis of 3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octanehydrochloride (S3b) The title compound S3b was prepared according to themethod presented for the synthesis of compound S1b but instead utilizingS3a. MS (ESI) m/z 316.1 [M+H]⁺.

Synthesis of 3-(5-iodopyridin-2-yl)-8-(oxetan-3-yl)-3,8diazabicyclo[3.2.1]octane (S3c)The title compound S3c was preparedaccording to the method presented for the synthesis of compound S1c butinstead utilizing S3b. MS (ESI) m/z 372.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.22 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.9, 2.4 Hz, 1H),6.30 (d, J=9.0 Hz, 1H), 4.65 (t, J=6.3 Hz, 2H), 4.52 (t, J=5.8 Hz, 2H),3.70 (dd, J=11.8, 2.4 Hz, 2H), 3.23-3.08 (m, 2H), 3.04 (dd, J=11.7, 2.2Hz, 2H), 1.87-1.70 (m, 2H), 1.63 (d, J=7.5 Hz, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S3) The title compound S3 was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing S3c.MS (ESI) m/z 244.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.16 (d,J=2.3 Hz, 1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H),4.76 (t, J=6.4 Hz, 3H), 4.57 (t, J=5.8 Hz, 3H), 3.88 (dd, J=12.2, 2.4Hz, 3H), 3.78 (ddd, J=11.9, 6.5, 5.4 Hz, 1H), 3.43 (s, 1H), 3.29 (dd,J=6.9, 1.7 Hz, 4H), 3.10 (dd, J=11.9, 2.2 Hz, 3H), 1.93 (dd, J=8.7, 4.4Hz, 2H), 1.68 (t, J=6.9 Hz, 2H).

Synthesis of3-(5-iodopyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane(S4a) The title compound S4a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizingtert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. MS (ESI) m/z358.0 [M+H]+.

Synthesis of3-(5-ethynylpyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane(S4). The title compound S4 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S4a. MS(ESI) m/z 256.2 [M+H]+. ¹H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J=2.3Hz, 1H), 7.53 (dd, J=8.9, 2.3 Hz, 1H), 6.55 (d, J=8.9 Hz, 1H), 4.65 (t,J=6.3 Hz, 2H), 4.36 (dd, J=6.3, 4.7 Hz, 2H), 3.77 (dd, J=19.2, 5.7 Hz,3H), 3.44 (s, 4H), 3.37 (s, 1H), 2.61 (dt, J=9.1, 6.2 Hz, 1H), 1.54 (d,J=9.1 Hz, 1H).

Synthesis of tert-butyl((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)(methyl)carbamate (S5a) To asolution of N-(tert-butoxycarbonyl)-N-methylglycine (4.81 g, 25.41 mmol)and 2,4′-dibromoacetophenone (6.42 g, 23.1 mmol) in MeCN (50 ml) wasadded Et₃N 9 (3.84 ml, 0.03 mol), the mixture was stirred for 5 min(small exotherm), then warmed to 30° C. The mixture was cooled to roomtemperature, diluted with EtOAc and washed saturated NH4Cl, saturatedNaHCO₃, and brine, then dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was suspended in a mixture ofisoopropanol (10 ml) and toluene (100 ml) and ammonium acetate (37 g,0.48 mol) was added, the reaction was refluxed for 4 h. Cooled to roomtemperature diluted with isopropyl acetate, washed with water, driedover Na₂SO₄, filtered, concentrated under reduced pressure and theresidue was purified by column chromatography (50% to 100%EtOAc/Hexanes) to afford S5a (8.0 g, 90%) MS (ESI) m/z 368 [M+H]⁺. 1HNMR (400 MHz, Methanol-d4) δ 7.61 (d, J=8.1 Hz, 2H), 7.54-7.45 (m, 2H),7.40 (s, 1H), 4.50 (s, 2H), 2.91 (s, 3H), 1.45 (d, J=21.0 Hz, 9H).

Synthesis of tert-butylmethyl((4-(4-((trimethylsily)ethynyl)phenyl)-1H-imidazol-2-yl)methyl)carbamate(S5b) A solution of S5a (8 g, 0.02 mol), CuI (0.249 g, 1.0 mmol),PdCl₂(tBu₂PPh)₂ (0.408 g, 0.655 mmol), trimethylsilylacetylene (12.44ml, 0.09 mol) in a mixture of CH₃CN/Et₃N 3:1 (50 mL) was degassed withArgon for 10 min. The reaction mixture was heated to 65° C. overnight.The reaction was diluted with EtOAc and washed with NaHCO3 solution anddried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue was used for the next step without purification (5.85 g,70%). MS (ESI) m/z 384.3 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.66(d, J=8.0 Hz, 2H), 7.45-7.31 (m, 3H), 4.84 (s, 2H), 2.91 (s, 4H), 1.46(s, 9H), 0.23 (s, 9H).

Synthesis of 2-(4-ethynylphenyl)-7-methyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one (S5) To an ice cooled solution of S5b (1450 mg,0 mol) in 2-methyl tetrahydrofuran (3 ml) was added sodium hydride (60%,0.21 g, 0.01 mol). After 10 min, methyl bromoacetate (0.72 ml, 0.01 mol)was added; the mixture was stirred for 5 min then warmed up to roomtemperature. After 30 min the reaction was diluted with EtOAc, rinsedwith brine, dried over Na₂SO₄, filtered, concentrated under reducedpressure and the residue was purified by column chromatography (20% to55% EtOAc/Hexanes). The product was dissolved in DCE (10 ml) and HCl(4.0M in dioxane, 11.69 ml) warmed to 25 C. After 2 h the reaction wasconcentrated under vacuo. The residue was dissolved in DMF (10 ml),Cesium carbonate (3.05 g, 0.01 mol) was added, warmed up 65 C for 45min, cooled to room temperature added MeOH (10 mL), stir 25 min. Slowlydilute with ˜40 mL water, stir 20 min. Filter off precipitated solids,rinsing with 30% MeOH in water. Concentrated under reduce pressure andthe crude material was carried on without further purification (0.479 g,62%) MS (ESI) m/z 252.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.69 (d,J=8.0 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 4.65 (s, 2H), 4.56(s, 2H), 4.11 (s, 1H), 2.95 (s, 3H).

Synthesis of(1R,4R)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S6a) The title compound S6a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizingtert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS(ESI) m/z 358.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.25 (dd,J=2.3, 0.8 Hz, 1H), 7.61 (ddd, J=8.8, 2.3, 0.6 Hz, 1H), 6.18 (dd, J=8.8,0.8 Hz, 1H), 4.71-4.58 (m, 3H), 4.52 (t, J=6.1 Hz, 1H), 4.45 (t, J=5.9Hz, 1H), 4.05-3.85 (m, 1H), 3.55 (d, J=2.4 Hz, 1H), 3.43-3.18 (m, 2H),2.94 (dd, J=9.5, 2.0 Hz, 1H), 2.83 (dd, J=9.4, 1.4 Hz, 1H), 2.00-1.89(m, 1H), 1.89-1.80 (m, 1H), 1.39 (t, J=7.3 Hz, 1H).

Synthesis of(1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S6) The title compound S6 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S6a. MS(ESI) m/z 256.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.13 (dd,J=2.2, 0.9 Hz, 1H), 7.37 (dd, J=8.7, 2.3 Hz, 1H), 6.23-5.98 (m, 1H),4.54 (dt, J=12.8, 6.5 Hz, 3H), 4.39 (t, J=6.1 Hz, 1H), 4.32 (t, J=5.9Hz, 1H), 3.90-3.75 (m, 1H), 3.31-3.10 (m, 2H), 2.93 (s, 1H), 2.82 (dd,J=9.5, 2.0 Hz, 1H), 2.73-2.60 (m, 1H), 1.82 (ddt, J=9.7, 2.4, 1.2 Hz,1H), 1.73 (ddt, J=9.8, 2.5, 1.2 Hz, 1H).

Synthesis of3-(5-iodopyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2. 1]octane(S7a) The title compound S7a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing2-chloro-5-iodopyrimidine. MS (ESI) m/z 373.0 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.37 (s, 2H), 4.71 (t, J=6.3 Hz, 2H), 4.59 (s, 2H), 4.21(d, J=12.4 Hz, 2H), 3.68 (s, 1H), 3.15 (s, 4H), 1.83 (s, 2H), 1.62 (s,2H).

Synthesis of3-(5-ethynylpyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S7) The title compound S7 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S7a. MS(ESI) m/z 271.1[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H),4.71 (t, J=6.2 Hz, 2H), 4.67-4.46 (m, 2H), 4.40-4.24 (m, 2H), 3.69 (p,J=6.1 Hz, 1H), 3.29-3.10 (m, 4H), 1.89-1.73 (m, 2H), 1.74-1.47 (m, 2H).

Synthesis of(R)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S8a).The title compound S8a was prepared according to the method presentedfor the synthesis of compound S1a but instead utilizing(R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride. MS (ESI) m/z346.1 [M+H]⁺.

Synthesis of (R)-8-(5-ethynylpyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S8). The title compound S8 wasprepared according to the method presented for the synthesis of compoundS1 but instead utilizing S8a. MS (ESI) m/z 244.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 8.30 (dd, J=2.3, 0.8 Hz, 1H), 7.54 (dd, J=8.8, 2.3Hz, 1H), 6.56 (dd, J=8.9, 0.8 Hz, 1H), 4.23-4.04 (m, 2H), 3.88 (dd,J=11.4, 3.4 Hz, 1H), 3.81 (dd, J=11.1, 3.1 Hz, 1H), 3.73 (t, J=11.5 Hz,1H), 3.32 (t, J=10.6 Hz, 1H), 3.13-3.01 (m, 2H), 2.86 (d, J=11.4 Hz,1H), 2.72 (d, J=11.5 Hz, 1H), 2.54 (t, J=11.7 Hz, 1H), 2.49-2.25 (m,2H).

Synthesis of(S)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S9a).The title compound S9a was prepared according to the method presentedfor the synthesis of compound S1a but instead utilizing(R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride. MS (ESI) m/z346.1 [M+H]⁺.

Synthesis of (S)-8-(5-ethynylpyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S9). The title compound S9 wasprepared according to the method presented for the synthesis of compoundS1 but instead utilizing S9a. MS (ESI) m/z 244.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 8.30 (dd, J=2.3, 0.8 Hz, 1H), 7.54 (dd, J=8.8, 2.3Hz, 1H), 6.56 (dd, J=8.9, 0.8 Hz, 1H), 4.23-4.04 (m, 2H), 3.88 (dd,J=11.4, 3.4 Hz, 1H), 3.81 (dd, J=11.1, 3.1 Hz, 1H), 3.73 (t, J=11.5 Hz,1H), 3.32 (t, J=10.6 Hz, 1H), 3.13-3.01 (m, 2H), 2.86 (d, J=11.4 Hz,1H), 2.72 (d, J=11.5 Hz, 1H), 2.54 (t, J=11.7 Hz, 1H), 2.49-2.25 (m,2H).

1-(5-iodopyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10a).1-benzyl-4-(3-methyloxetan-3-yl)piperazine (6.75 g, 27.4 mmol),palladium (10% on carbon, 1.46 g, 1.37 mmol) in EtOH (55 ml) werecombined in a PARR flask and shaken on the hydrogenator overnight at 45PSI. The reaction was filtered over Celite, the filter cake was washedwith 25% MeOH/DCM and the filtrate was concentrated under reducedpressure. The residue was combined 2-fluoro-5-iodopyridine to preparethe title compound S10a according to the method presented for thesynthesis of compound S1a. MS (ESI) m/z 360.0 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 6.48 (d,J=9.0 Hz, 1H), 4.62 (d, J=5.5 Hz, 2H), 4.26 (d, J=5.5 Hz, 2H), 3.54 (s,4H), 2.44 (s, 5H), 1.37 (s, 3H).

1-(5-ethynylpyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10). Thetitle compound S10 was prepared according to the method presented forthe synthesis of compound S1 but instead utilizing S10a. MS (ESI) m/z258.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J=2.3, 0.8 Hz,1H), 7.56 (dd, J=8.9, 2.3 Hz, 1H), 6.76 (dd, J=9.0, 0.8 Hz, 1H),4.78-4.52 (m, 2H), 4.28 (d, J=5.9 Hz, 2H), 3.65-3.48 (m, 4H), 3.43 (s,1H), 2.59-2.39 (m, 4H), 1.38 (d, J=0.7 Hz, 3H).

Synthesis of3-(5-iodopyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S11a). A solution of S3b (1.0 g, 3.173 mmol),(R)-tetrahydrofuran-3-yl methanesulfonate (965 mg, 5.807 mmol), andpotassium carbonate (1754 mg, 12.69 mmol) in CH₃CN (15 mL) was heated atreflux for 48 h. The reaction mixture cooled to room temperature,diluted with EtOAc and washed with brine. The organic extract was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (0% to 5% MeOH/EtOAc) toafford S11a (355.2 mg, 29%) MS (ESI) m/z 386.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.22 (dd, J=2.3, 0.7 Hz, 1H), 7.56 (dd, J=8.9, 2.4 Hz,1H), 6.29 (dd, J=9.0, 0.7 Hz, 1H), 3.96-3.84 (m, 2H), 3.76 (dt, J=8.6,7.6 Hz, 1H), 3.62 (ddd, J=11.5, 8.9, 2.5 Hz, 2H), 3.55 (dd, J=8.2, 6.9Hz, 1H), 3.33 (d, J=4.7 Hz, 1H), 3.20 (d, J=3.4 Hz, 1H), 3.11-2.97 (m,3H), 2.02 (dtd, J=12.1, 7.4, 4.7 Hz, 1H), 1.95-1.87 (m, 2H), 1.87-1.72(m, 1H), 1.67-1.56 (m, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane(S11). The title compound S11 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S11a.MS (ESI) m/z 284.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.22-8.10 (m,1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.65 (dd, J=9.1, 0.8 Hz, 1H), 3.97(td, J=8.1, 4.5 Hz, 2H), 3.89-3.74 (m, 3H), 3.63 (dd, J=8.4, 6.6 Hz,1H), 3.48 (d, J=4.4 Hz, 1H), 3.42 (s, 1H), 3.35 (s, 1H), 3.26-3.19 (m,1H), 3.12 (dt, J=12.2, 3.5 Hz, 2H), 2.15 (ddd, J=11.8, 8.2, 4.5 Hz, 1H),2.03 (dd, J=14.4, 7.3 Hz, 2H), 1.85 (dq, J=12.0, 7.8 Hz, 1H), 1.69 (d,J=9.1 Hz, 2H).

Synthesis of3-(5-iodopyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S12a). The title compound S12a was prepared according to themethod presented for the synthesis of compound S11a but insteadutilizing (S)-tetrahydrofuran-3-yl methanesulfonate. MS (ESI) m/z 386.1[M+H]⁺. 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.3 Hz, 1H), 7.62(dd, J=9.0, 2.4 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 4.04-3.91 (m, 2H),3.90-3.75 (m, 1H), 3.68 (ddd, J=11.6, 8.8, 2.5 Hz, 2H), 3.61 (dd, J=8.2,6.9 Hz, 1H), 3.39 (q, J=2.7 Hz, 1H), 3.26 (dt, J=5.0, 2.1 Hz, 1H),3.18-3.04 (m, 3H), 2.17-2.01 (m, 1H), 1.97 (dd, J=9.4, 5.6 Hz, 2H),1.90-1.77 (m, 1H), 1.74-1.63 (m, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8diazabicyclo[3.2.1]octane (S12). The title compound S12 was prepared according to themethod presented for the synthesis of compound S1 but instead utilizingS12a. MS (ESI) m/z 284.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.22-8.07 (m, 1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.65 (dd, J=8.8, 0.9Hz, 1H), 3.96 (td, J=8.1, 4.5 Hz, 2H), 3.88-3.74 (m, 3H), 3.63 (dd,J=8.4, 6.6 Hz, 1H), 3.48 (s, 1H), 3.42 (s, 1H), 3.35 (s, 1H), 3.24 (t,J=7.0 Hz, 1H), 3.12 (dt, J=12.1, 3.4 Hz, 2H), 2.26-2.09 (m, 1H), 2.03(dd, J=14.1, 7.5 Hz, 2H), 1.85 (dq, J=12.0, 8.0 Hz, 1H), 1.69 (d, J=9.1Hz, 2H).

Synthesis of3-(5-iodopyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S13a) A suspension of S3b (3 g, 9.519 mmol), diethyl2-bromo-2-methylmalonate (2.25 ml, 11.78 mmol), and sodium carbonate(1.19 g, 19.19 mmol) in NMP (30 mL) in a 100 ml sealed tube was stirredat 70° C. for 48 h. The reaction mixture was cooled to room temperature,diluted with EtOAc and washed with brine 2×. The organic extract wasdried over Na₂SO₄ filtered, and the crude residue was purified by silicacolumn chromatography (10%-20% EtOAc/hexanes) to afford diethyl2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylmalonate(2.32 g, 50%). MS (ESI) m/z 488.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d)δ 8.27 (dd, J=2.4, 0.7 Hz, 1H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.51-6.27(m, 1H), 4.37-4.07 (m, 4H), 3.84 (s, 2H), 3.79-3.72 (m, 2H), 3.29-3.07(m, 2H), 1.77-1.63 (m, 4H), 1.62 (s, 3H), 1.27 (t, J=7.2 Hz, 6H).

To a solution of diethyl2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylmalonate(907.9 mg, 1.863 mmol) in DCM (40 mL) at −78° C. was added Dibal-H (1.0M in toluene, 93 ml). The reaction was gradually warmed to roomtemperature and stirred overnight. Dibal-H (1.0 M in DCM, 16 ml) wasadded, stirred for 1h, and then cooled to 0° C. diluted with Et₂O.Slowly added water (4.4 mL), 15% NaOH (4.4 mL), followed by water (10.9mL), warmed to room temperature and stirred for 15 min. Added Na₂SO₄,stirred for 15 min, then filtered off salts to give2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropane-1,3-diol(2.059 g, 65%). MS (ESI) m/z 404.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 8.18 (dd, J=2.4, 0.7 Hz, 1H), 7.69 (dd, J=9.0, 2.4 Hz, 1H), 6.54 (d,J=9.1 Hz, 1H), 3.91-3.66 (m, 4H), 3.49 (s, 4H), 3.10-2.88 (m, 2H), 1.83(d, J=8.8 Hz, 2H), 1.72 (t, J=6.6 Hz, 2H), 1.00 (s, 3H).

To a solution of2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropane-1,3-diol(2.06 g, 5.106 mmol) and triethylamine (1.5 ml , 10.76 mmol) in THF (25mL) at 0° C. was added methanesulfonyl chloride (0.40 ml, 5.169 mmol).The reaction was gradually warmed to room temperature and stirredovernight. The reaction mixture was diluted with EtOAc and washed withbrine. The organic extract was dried over Na₂SO₄, filtered, and thecrude residue was purified by silica column chromatography (25% -50%EtOAc/hexanes) to afford3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol(441.6 mg, 20.5%). MS (ESI) m/z 422.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.27 (dd, J=2.4, 0.7 Hz, 1H), 7.62 (dd, J=8.9, 2.4 Hz,1H), 6.35 (dd, J=9.0, 0.7 Hz, 1H), 4.63 (s, 1H), 3.90-3.63 (m, 4H), 3.56(d, J=5.1 Hz, 1H), 3.35 (s, 1H), 3.06 (dt, J=11.8, 3.0 Hz, 2H), 2.87 (t,J=13.5 Hz, 1H), 2.66 (d, J=14.0 Hz, 1H), 1.88 (dt, J=9.9, 4.9 Hz, 2H),1.76-1.63 (m, 2H), 1.57 (s, 3H).

To a solution of3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol(418.5 mg, 0.992 mmol) in THF (10 mL) at 0° C., was added potassiumtert-butoxide (1.0 M THF, 3 ml). After 10 min the reaction mixture wasquenched with water, diluted with EtOAc and washed with brine. Theorganic extract was dried over Na₂SO₄, filtered, and the crude residuewas purified by silica column chromatography (50%-100% EtOAc/hexanes) toafford S13a (222.8 mg, 58% yield). MS (ESI) m/z 386.1 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) δ 8.27 (dd, J=2.4, 0.7 Hz, 1H), 7.61 (dd, J=9.0,2.4 Hz, 1H), 6.35 (dd, J=9.0, 0.7 Hz, 1H), 3.68 (ddd, J=11.5, 4.4, 2.6Hz, 2H), 3.49-3.34 (m, 1H), 3.30 (q, J=2.7 Hz, 1H), 3.07 (dd, J=11.6,2.5 Hz, 2H), 2.70 (dd, J=5.0, 0.7 Hz, 1H), 2.64-2.53 (m, 2H), 2.39 (d,J=13.2 Hz, 1H), 1.96-1.79 (m, 2H), 1.68-1.57 (m, 2H), 1.42 (d, J=0.6 Hz,3H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S13). The title compound S13 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S13a.MS (ESI) m/z 284.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.15 (dd,J=2.3, 0.8 Hz, 1H), 7.53 (dd, J=8.9, 2.3 Hz, 1H), 6.64 (dd, J=9.0, 0.8Hz, 1H), 3.91-3.74 (m, 3H), 3.50-3.43 (m, 1H), 3.42 (s, 1H), 3.39-3.32(m, 1H), 3.08 (dt, J=11.7, 1.9 Hz, 3H), 2.72 (dd, J=4.9, 0.7 Hz, 2H),2.66 (d, J=13.3 Hz, 1H), 2.60 (d, J=4.9 Hz, 1H), 2.43 (d, J=13.3 Hz,1H), 1.94 (dd, J=9.4, 5.5 Hz, 3H), 1.69-1.57 (m, 2H), 1.42 (d, J=0.6 Hz,4H).

Synthesis of 1-(5-bromopyridin-2-yl)piperazine hydrochloride (S14a) To asolution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate(5 g, 14.61 mmol) in DCM (60 mL) and MeOH (18 mL), was added HCl (4.0 Min dioxanes, 18 mL, 72 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM and washed with2N NaOH. The aqueous layer was extracted with DCM 2× and the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduce pressure to afford S14a (3.2 g, 90.4%). MS (ESI) m/z 242.1 ([M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.18 (dd, J=2.6, 0.7 Hz, 1H),7.52 (dd, J=9.0, 2.6 Hz, 1H), 6.53 (dd, J=9.1, 0.7 Hz, 1H), 3.54-3.40(m, 4H), 3.09-2.87 (m, 4H).

Synthesis of(R)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14b).The title compound S14a was prepared according to the method presentedfor the synthesis of compound S11a but instead utilizing S14a and(S)-tetrahydrofuran-3-yl methanesulfonate. MS (ESI) m/z 312.1 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 8.19 (dd, J=2.6, 0.7 Hz, 1H), 7.53 (dd,J=9.0, 2.5 Hz, 1H), 6.54 (dd, J=9.0, 0.7 Hz, 1H), 3.96 (td, J=8.6, 4.4Hz, 1H), 3.91 (dd, J=8.7, 6.8 Hz, 1H), 3.80 (td, J=8.4, 7.5 Hz, 1H),3.69 (t, J=7.7 Hz, 1H), 3.52 (t, J=5.3 Hz, 4H), 3.01 (t, J=7.3 Hz, 1H),2.63 (d, J=9.9 Hz, 2H), 2.57-2.46 (m, 2H), 2.07 (ddd, J=9.9, 7.1, 3.3Hz, 1H), 1.90 (q, J=11.1, 9.5 Hz, 1H).

Synthesis of(R)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14).The title compound S14 was prepared according to the method presentedfor the synthesis of compound S1 but instead utilizing S14b. MS (ESI)m/z 258.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J=2.3 Hz,1H), 7.56 (dd, J=8.8, 2.3 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 3.95 (dt,J=8.5, 4.3 Hz, 1H), 3.90 (dd, J=8.8, 7.0 Hz, 2H), 3.76 (q, J=8.2 Hz,1H), 3.68 (dd, J=8.8, 6.6 Hz, 1H), 3.58 (t, J=5.2 Hz, 4H), 3.43 (s, 1H),3.09-2.97 (m, 1H), 2.65 (dt, J=10.6, 5.2 Hz, 2H), 2.54 (dt, J=11.2, 5.2Hz, 2H), 2.20-2.06 (m, 1H), 1.96-1.83 (m, 1H).

Synthesis of(S)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15a).The title compound S15a was prepared according to the method presentedfor the synthesis of compound S11a but instead utilizing S14a. MS (ESI)m/z 312.2 [M+H]^(|). ¹H NMR (400 MHz, Chloroform-d) δ 8.18 (dd, J=2.6,0.7 Hz, 1H), 7.52 (dd, J=9.0, 2.6 Hz, 1H), 6.53 (dd, J=9.1, 0.7 Hz, 1H),3.96 (td, J=8.6, 4.4 Hz, 1H), 3.91 (dd, J=8.6, 6.8 Hz, 1H), 3.80 (td,J=8.4, 7.5 Hz, 1H), 3.68 (dd, J=8.7, 6.7 Hz, 1H), 3.52 (dd, J=5.9, 4.5Hz, 4H), 3.00 (p, J=7.1 Hz, 1H), 2.63 (dt, J=10.7, 5.2 Hz, 2H), 2.50(dt, J=10.8, 5.1 Hz, 2H), 2.17-1.99 (m, 1H), 1.99-1.79 (m, 1H).

Synthesis of(S)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15)).The title compound S15 was prepared according to the method presentedfor the synthesis of compound S1 but instead utilizing S15a. MS (ESI)m/z 258.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.09 (dd, J=2.4, 0.8Hz, 1H), 7.47 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (dd, J=9.0, 0.8 Hz, 1H),3.86 (dt, J=8.6, 4.3 Hz, 1H), 3.80 (dd, J=8.9, 7.0 Hz, 2H), 3.67 (td,J=8.4, 7.2 Hz, 1H), 3.59 (dd, J=8.7, 6.6 Hz, 1H), 3.49 (t, J=5.2 Hz,4H), 3.34 (s, 1H), 3.02-2.86 (m, 1H), 2.55 (dt, J=10.7, 5.2 Hz, 2H),2.44 (dt, J=11.1, 5.2 Hz, 2H), 2.10-1.94 (m, 2H), 1.86-1.71 (m, 2H).

Synthesis of tert-butyl3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(S16). The title compound S16 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S3a. MS(ESI) m/z 313.9 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J=2.3,0.8 Hz, 1H), 7.56 (dd, J=8.9, 2.3 Hz, 1H), 6.69 (dd, J=8.9, 0.9 Hz, 1H),4.45-4.30 (m, 2H), 4.04-3.95 (m, 2H), 3.43 (s, 1H), 3.02 (d, J=12.2 Hz,2H), 1.94 (dd, J=8.7, 4.4 Hz, 2H), 1.75 (d, J=7.3 Hz, 2H), 1.48 (s, 9H).

Synthesis of tert-butyl6-(5-iodopyridin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (S17a). Thetitle compound S17a was prepared according to the method presented forthe synthesis of compound S1a but instead utilizing tert-Butyl2,6-diazaspiro[3.3]heptane-2-carboxylate. MS (ESI) m/z 401.9 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.2 Hz, 1H), 7.67 (d, J=8.7 Hz,1H), 6.14 (d, J=8.7 Hz, 1H), 4.13 (s, 4H), 4.10 (s, 4H), 1.44 (s, 9H).

Synthesis of6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-azaspiro[3.3]heptane(S17b). A solution of S17a (1.048 mg, 2.612 mmol), CuI (0.111 g, 0.583mmol), PdCl₂(tBu₂PPh)₂ (0.163 g, 0.261 mmol), TMSA (2.1 ml, 14.75 mmol),Et₃N (2.7 ml, 19.48 mmol) in CH₃CN (20 mL) at 0° C. was degassed withArgon for 10 min. The reaction mixture stirred at reflux overnight, thencooled to room temperature, diluted with EtOAc, washed with NaHCO₃solution and dried over Na₂SO₄, filtered, concentrated under reducedpressure and the residue was purified by silica column chromatography(20% to 40% EtOAc/Hex) to give (760 mg, 78%) of desired product. Thisproduct (0.4 g, 1076.58 μmol) was dissolved in DCM (5 mL) andtrifluoroacetic acid (1000 μl, 13.07 mmol) was added, the mixture wasstirred at 0° C. After 4 h, the reaction mixture was concentrated underreduced pressure, diluted with toluene (5 mL) and concentrated to affordS17b (0.54 g, 100.1%). MS (ESI) m/z 272.1 [M+H]⁺.

Synthesis of6-(5-ethynylpyridin-2-yl)-2-(oxetan-3-yl)-2-azaspiro[3.3]heptane (S17) Asuspension of S17b (538 mg, 1.08 mmol) with triethylamine (0.3 ml, 2.154mmol) in 2-Me THF (4 mL) and AcOH (0.2 mL), was added oxetan-3-one (234mg, 3.247 mmol) in 2-Me-THF (1 mL) followed by sodium cyanoborohydride(209 mg, 3.326 mmol). The reaction was stirred at room temperature.After 18 h, the reaction mixture was quenched with NaHCO3 solution andpartitioned with EtOAc. The organic extract was dried over Na₂SO₄,filtered, concentrated under reduced pressure and the residue waspurified by silica column chromatography (50% to 75% EtOAc/Hex). Theproduct was dissolved in MeOH (5 mL), Potassium carbonate (0.28 g, 2.05mmol) was added and the mixture was stirred at room temperature. After48h the reaction mixture was concentrated under reduced pressure,diluted with EtOAc, washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was dissolved inmethanol (2.0 mL) and sodium hydroxide solution (2M, 2 ml) was added,warmed up to 70° C. for 18 h. The reaction was cooled to roomtemperature concentrated under reduced pressure; the residue was dilutedwith EtOAc, washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford S17 MS (ESI) m/z 256.1[M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.09 (dd, J=2.2, 0.8 Hz, 1H),7.55 (dd, J=8.7, 2.2 Hz, 1H), 6.36 (dd, J=8.7, 0.8 Hz, 1H), 4.72 (td,J=6.7, 0.5 Hz, 3H), 4.45 (ddd, J=6.8, 4.9, 0.6 Hz, 3H), 4.13 (s, 5H),3.76 (tt, J=6.5, 4.9 Hz, 1H), 3.50 (s, 5H), 3.44 (s, 1H).

Synthesis of tert-butyl(3aR,6aS)-5-(5-iodopyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(S18a) The title compound S18a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizingtert-butyl (3aR,6aS)-hexahydropyrrolo [3,4-c]pyrrole-2(1H)-carboxylate.MS (ESI) m/z 415.8 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.28 (dd,J=2.4, 0.8 Hz, 1H), 7.63 (dd, J=8.9, 2.3 Hz, 1H), 6.19 (d, J=8.9 Hz,1H), 3.66 (dd, J=10.7, 7.0 Hz, 4H), 3.51-3.17 (m, 4H), 2.99 (d, J=5.9Hz, 2H), 1.45 (s, 9H).

Synthesis of(3aR,6aS)-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole(S18b). A solution of S18a (0.986 g, 2.374 mmol), CuI (0.099 g, 0.522mmol), PdCl₂(tBu₂PPh)₂ (0.148 g, 0.237 mmol), TMSA (1.9 ml, 13.35 mmol),Et₃N (2.5 ml, 18.04 mmol) in CH₃CN (8 mL) was degassed with Argon for 10min. The reaction mixture was heated to 60° C. and stirred overnight.The reaction was diluted with EtOAc and washed with NaHCO3 solution,dried over Na₂SO₄, filtered, and concentrated under reduced pressure andthe residue was purified by silica column chromatography (10% to 30%EtOAc/Hex), the product (0.68 g, 1.75 mmol) was dissolved in a mixtureof DCM (8 mL) and MeOH (2 mL) and HCl (4.0 M in dioxanes, 2 ml) wasadded. The reaction was stirred for 18 h, diluted with DCM, washed with2N NaOH solution. The aqueous layer was re-extracted with DCM and thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford S18b (0.56 g, 112.7%). MS(ESI) m/z 286.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.82 (dd, J=2.1,0.7 Hz, 1H), 7.73 (dd, J=9.5, 2.1 Hz, 1H), 6.88 (dd, J=9.5, 0.9 Hz, 1H),3.78-3.63 (m, 2H), 3.59-3.48 (m, 2H), 3.46-3.34 (m, 3H), 3.25-3.10 (m,3H), -0.00 (s, 9H).

Synthesis of(3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole(S18). To a solution of S18b (0.25 g, 0.701 mmol) in DCE (6 mL) wasadded formaldehyde solution (0.30 ml, 8.143 mmol) and acetic acid (0.025ml, 4.367 mmol). The reaction mixture was heated at 60° C. for 30 min.Cooled to room temperature and added sodium cyanoborohydride (165.1 mg,2.63 mmol). The reaction was heated at 60° C. for 45 min, then cooled toroom temperature, diluted with EtOAc, washed with brine, back-extractedthe aqueous layer with EtOAc, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure the residue was dissolved in MeOH (5mL) and Potassium carbonate (0.29 g, 2.1 mmol) was added, the reactionmixture was stirred at room temperature. After 18 h, the reaction wasconcentrated under reduced pressure and the residue was diluted withEtOAc, washed with brine dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford S18 (0.15 g, 87%). MS (ESI) m/z 228.1[M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.19 (dd, J=2.3, 0.8 Hz, 1H),7.60 (dd, J=8.8, 2.3 Hz, 1H), 6.58 (dd, J=8.9, 0.8 Hz, 1H), 3.70-3.59(m, 1H), 3.54-3.45 (m, 3H), 3.10 (s, 3H), 2.97-2.84 (m, 2H), 2.54 (dd,J=9.7, 4.0 Hz, 2H), 2.39 (s, 3H).

Synthesis of(3aR,6aS)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole(S19a) The title compound S19a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing S18a.MS (ESI) m/z 372.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.17 (dd,J=2.3, 0.7 Hz, 1H), 7.71 (ddd, J=8.9, 2.3, 0.8 Hz, 1H), 6.43 (dd, J=9.0,0.7 Hz, 1H), 4.69 (t, J=6.6 Hz, 2H), 4.64-4.55 (m, 2H), 3.70-3.60 (m,1H), 3.59-3.49 (m, 2H), 3.38 (dd, J=10.8, 3.1 Hz, 2H), 3.02 (td, J=7.3,3.7 Hz, 2H), 2.88-2.71 (m, 2H), 2.42 (dd, J=9.4, 4.0 Hz, 2H).

Synthesis of(3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole(S19). The title compound S19 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S19a.MS (ESI) m/z 270.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.05 (dd,J=2.2, 0.8 Hz, 1H), 7.46 (dd, J=8.8, 2.3 Hz, 1H), 6.43 (dd, J=8.9, 0.8Hz, 1H), 4.68-4.58 (m, 2H), 4.59-4.44 (m, 2H), 3.64-3.45 (m, 2H),3.40-3.30 (m, 4H), 2.95 (dq, J=7.5, 3.9 Hz, 2H), 2.70 (dd, J=9.6, 7.1Hz, 1H), 2.36 (dd, J=9.5, 4.0 Hz, 2H).

Synthesis of3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octanehydrochloride (S20a) The title compound S20a was prepared according tothe method presented for the synthesis of compound S19a but insteadutilizing S3a. MS (ESI) m/z 286.1 [M+H]⁺.

Synthesis of3-(5-ethynylpyridin-2-yl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (S20)To a solution of S20a (0.2 g, 0.7 mmol) in THF (6 mL) was addedformaldehyde solution (0.13 ml, 3.5 mmol) and acetic acid (0.03 ml, 0.51mmol). The reaction mixture stirred at room temperature overnight.Sodium cyanoborohydride (132.09 mg, 2.1 mmol) was added. After 5 h, MeOH(2 mL) and NaOH (2 N, 2 mL) were added and the mixture was stirred foranother 18 h. The reaction was concentrated under reduced pressure,diluted with EtOAc, washed with brine, back-extracted the aqueous layerwith EtOAc, dried over Na₂SO₄, filtered, concentrated under reducedpressure and the residue was purified by silica column chromatography(100% EtOAc to 5%-10% MeOH/EtOAc) to give S20 (62.6 mg, 39.3%). MS (ESI)m/z 228.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.16 (dd, J=2.4,0.8 Hz, 1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (dd, J=8.9, 0.9 Hz, 1H),3.86 (dd, J=12.5, 2.4 Hz, 3H), 3.42 (s, 1H), 3.08 (dd, J=12.3, 2.3 Hz,3H), 2.36 (d, J=2.4 Hz, 3H), 2.07 (dt, J=7.1, 3.2 Hz, 2H), 1.68 (t,J=6.8 Hz, 2H).

Synthesis of8-ethyl-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S21) Toa solution of S20a (0.24 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) wasadded acetaldehyde (0.5 ml, 8.90 mmol) and acetic acid (0.04 ml, 0.7mmol). After 18 h sodium cyanoborohydride (314 mg, 5.0 mmol) was added.Stirred overnight, diluted with EtOAc, washed with brine, back-extractedthe aqueous layer with EtOAc, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure and the residue was purified bysilica column chromatography (10%-20% MeOH/EtOAc) to give (0.12 g, 0.39mmol) of product which was dissolved in MeOH (5 mL) and potassiumcarbonate (0.16 g, 1.17 mmol) was added, the reaction mixture wasstirred at room temperature. After 3 h, the reaction was concentratedunder reduced pressure and the residue was diluted with EtOAc, washedwith brine dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford S21 (0.09 g, 44%). MS (ESI) m/z 242.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.16 (dd, J=2.3, 0.8 Hz, 1H), 7.55 (dd, J=8.9,2.3 Hz, 1H), 6.65 (dd, J=8.9, 0.9 Hz, 1H), 3.85 (dd, J=12.5, 2.4 Hz,2H), 3.44 (dd, J=4.6, 2.5 Hz, 2H), 3.41 (s, 1H), 3.09 (dd, J=12.2, 2.2Hz, 2H), 2.52 (q, J=7.2 Hz, 2H), 2.00 (dt, J=7.0, 3.1 Hz, 2H), 1.67 (t,J=6.8 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-isopropyl-3,8-diazabicyclo[3.2.1]octane(S22) To a solution of S20a (0.1 g, 0.35 mmol) in Methanol (1.2 ml) wasadded sodium acetate (28.74 mg, 0.35 mmol), acetic acid (21.04 mg, 0.35mmol) and acetone (20.35 mg, 0.35 mmol) the mixture was stirred at 40°C. After 1 h sodium cyanoborohydride (44.03 mg, 0.7 mmol) was added andthe reaction was stirred at 40° C. After 12 h the mixture was cooled toroom temperature, concentrated under reduce pressure and the residue wasdiluted with EtOAc, washed with saturated NaHCO3 solution, dried overNa₂SO₄, filtered, and concentrated under reduced pressure and purifiedby silica column chromatography (2% MeOH/EtOAc). The product wasdissolved in Methanol (1 ml), potassium carbonate (0.05 g, 0.35 mmol)was added and after 1 h the mixture was concentrated diluted with EtOAc,washed with water, dried over Na2SO4, filtered concentrated to yield S22(28 mg, 31.3%). MS (ESI) m/z 256.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄)δ 8.18 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.9, 2.4 Hz, 1H), 6.68 (d, J=8.9Hz, 1H), 3.93-3.68 (m, 6H), 3.43 (s, 1H), 3.23-3.12 (m, 3H), 2.86 (s,2H), 2.07-1.92 (m, 3H), 1.75 (t, J=6.6 Hz, 3H), 1.20 (d, J=6.4 Hz, 8H).

Synthesis of (2S,6R)-4-(5-iodopyridin-2-yl)-2,6-dimethylmorpholine(S23a) The title compound S23a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizing(2S,6R)-2,6-dimethylmorpholine. MS (ESI) m/z 319.0 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 8.32 (d, J=2.3 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H),6.49 (d, J=9.0 Hz, 1H), 4.00 (d, J=12.6 Hz, 2H), 3.70 (ddd, J=10.6, 6.3,2.6 Hz, 2H), 2.53 (t, J=11.6 Hz, 2H), 1.26 (d, J=6.2 Hz, 6H).

Synthesis of (2S,6R)-4-(5-ethynylpyridin-2-yl)-2,6-dimethylmorpholine(S23) The title compound S23 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S23a.MS (ESI) m/z 217.1 [M+H]⁺.

Synthesis of3-(5-ethynylpyridin-2-yl)-N,N-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide(S24) To a solution of S20a (200 mg, 0.558 mmol) and Et₃N (0.3 ml, 2.164mmol) in DCM (5 mL) at 0° C., was added dimethylcarbamoyl chloride(0.055 ml, 0.601 mmol). The reaction was gradually warmed to roomtemperature and stirred overnight. The reaction was concentrated underreduced pressure. The residue was dissolved in MeOH (5 mL) and K₂CO₃(313 mg, 2.236 mmol) was added. After stirring at room temperature for48 h, the reaction was concentrated, then diluted with EtOAc and washedwith brine. The organic extracts were dried over Na₂SO₄ to give S24(123.9 mg, 78%). MS (ESI) m/z 276.2 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d4) δ 8.17 (dd, J=2.3, 0.8 Hz, 1H), 7.55 (dd, J=8.9, 2.3 Hz,1H), 6.69 (dd, J=9.0, 0.8 Hz, 1H), 4.19 (dd, J=4.5, 2.2 Hz, 3H), 3.98(dd, J=12.4, 2.5 Hz, 3H), 3.42 (s, 1H), 3.11 (dd, J=12.2, 2.1 Hz, 3H),2.94 (s, 8H), 1.88 (dd, J=8.5, 4.4 Hz, 3H), 1.71 (q, J=6.7 Hz, 2H).

Synthesis of(3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((S)-tetrahydrofuran-2-yl)methanone(S25) To S20a suspended in CH₂Cl₂ (10 mL) was added(S)-tetrahydrofuran-2-carboxylic acid (0.12 ml, 1 mmol), Et₃N (0.68 ml,5 mmol) followed by HATU (0.48 g, 1 mmol). The mixture was stirred for1.5 h. The mixture was diluted with DCM and washed with water. Theorganic layer was dried over Na₂SO₄, and concentrated in vacuo. Theresidue was dissolved in MeOH (20 mL), cooled to 5° C. and potassiumcarbonate (0.4 g, 3 mmol) was added. After 30 min, the reaction quenchedwith water and brine, extracted into DCM, dried over Na₂SO₄, filtered,concentrated under reduced pressure and the residue was purified bysilica column chromatography (60%-100% EtOAc/hexanes to 5% MeOH/EtOAc)to give S25 (0.23 g, 74.3%). MS (ESI) m/z 312.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.29 (dd, J=2.3, 0.8 Hz, 1H), 7.54 (dt, J=8.9, 2.4 Hz,1H), 6.48 (d, J=8.8 Hz, 1H), 4.84 (t, J=8.6 Hz, 1H), 4.66 (d, J=6.8 Hz,1H), 4.56 (ddd, J=14.9, 7.4, 5.7 Hz, 2H), 4.12 (ddd, J=20.9, 12.7, 2.3Hz, 1H), 3.99-3.73 (m, 4H), 3.21 (dd, J=12.1, 2.3 Hz, 1H), 3.14 (dd,J=12.0, 2.4 Hz, 1H), 3.07 (s, 1H), 3.06-3.02 (m, 0H), 2.41-2.21 (m, 1H),2.15-1.70 (m, 5H).

Synthesis of tert-butyl8-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(S26a) The title compound S26a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizingtert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) m/z415.8 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.2 Hz, 1H),7.70 (s, 1H), 6.46 (s, 1H), 4.45 (s, 2H), 3.78 (d, J=52.7 Hz, 2H), 3.14(dd, J=50.9, 12.9 Hz, 2H), 2.06-1.77 (m, 4H), 1.45 (s, 12H).

Synthesis of8-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S26b). The title compound S26b was prepared according to the methodpresented for the synthesis of compound S17b but instead utilizing S26a.MS (ESI) m/z 286.2 [M+H]³⁰ .

Synthesis of8-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S26). The title compound S26 was prepared according to the methodpresented for the synthesis of compound S18 but instead utilizingoxetan-3-one. MS (ESI) m/z 270.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.18 (d, J=2.3 Hz, 1H), 7.58 (dd, J=8.8, 2.3 Hz, 1H), 6.73 (d, J=8.8 Hz,1H), 4.61 (dt, J=11.1, 5.5 Hz, 7H), 3.51-3.44 (m, 2H), 2.64 (dd, J=10.9,2.6 Hz, 3H), 2.23 (d, J=10.7 Hz, 2H), 2.14 (t, J=6.2 Hz, 2H), 1.99 (dd,J=8.3, 4.2 Hz, 2H).

Synthesis of 5-iodo-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27a). Thetitle compound S27a was prepared according to the method presented forthe synthesis of compound S1a but instead utilizing2-oxa-6-azaspiro[3.3]heptane. ¹H NMR (400 MHz, Chloroform-d) δ 8.16 (dd,J=2.4, 0.7 Hz, 1H), 7.52 (dd, J=8.8, 2.4 Hz, 1H), 6.20 (d, J=8.8 Hz,1H), 4.84 (s, 4H), 4.17 (s, 5H).

Synthesis of 5-ethynyl-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27). Thetitle compound S27 was prepared according to the method presented forthe synthesis of compound S1 but instead utilizing S27a. MS (ESI) m/z201.1 [M+H]⁺.

Synthesis of7-(5-ethynylpyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S28). Thetitle compound S28 was prepared according to the method presented forthe synthesis of compound S1 but instead utilizing S1b. MS (ESI) m/z230.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.56-7.43(m, 1H), 6.48 (d, J=8.9 Hz, 1H), 4.42 (d, J=13.5 Hz, 2H), 4.12 (d,J=12.1 Hz, 2H), 3.93 (d, J=12.2 Hz, 2H), 3.59 (d, J=13.6 Hz, 2H), 3.36(s, 2H), 3.00 (d, J=1.1 Hz, 1H).

Synthesis of(1R,4R)-2-(5-iodopyrimidin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S29a) The title compound S29a was prepared according to the methodpresented for the synthesis of compound S7a but instead utilizingtert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS(ESI) m/z 359.1 [M+H]⁺. 1H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 2H),4.79 (s, 1H), 4.69 (dt, J=10.0, 6.5 Hz, 2H), 4.55 (t, J=6.1 Hz, 1H),4.48 (t, J=5.9 Hz, 1H), 3.98 (p, J=6.3 Hz, 1H), 3.57 (s, 1H), 3.46 (dd,J=11.0, 1.6 Hz, 1H), 3.36 (dd, J=10.8, 2.0 Hz, 1H), 2.98 (dd, J=9.6, 2.0Hz, 1H), 2.82 (d, J=9.6 Hz, 1H), 1.97 (d, J=9.9 Hz, 1H), 1.86 (d, J=9.8Hz, 1H).

Synthesis of(1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S29) The title compound S29 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S29a.MS (ESI) m/z 257.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.39 (s,2H), 4.88 (s, 1H), 4.70 (dt, J=9.5, 6.5 Hz, 2H), 4.52 (dt, J=26.3, 6.0Hz, 2H), 3.99 (p, J=6.3 Hz, 1H), 3.58 (s, 1H), 3.52 (d, J=10.9 Hz, 1H),3.41 (dd, J=11.0, 2.0 Hz, 1H), 3.18 (s, 1H), 2.99 (d, J=9.6 Hz, 1H),2.83 (d, J=9.6 Hz, 1H), 1.98 (d, J=9.9 Hz, 1H), 1.87 (d, J=9.8 Hz, 1H).

Synthesis of(1S,4S)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S30a) The title compound S30a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizingtert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS(ESI) m/z 358.0 [M+H]⁺.

Synthesis of(1S,4S)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane(S30) The title compound S30 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S30a.MS (ESI) m/z 256.2 ( [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.12 (dd,J=2.3, 0.8 Hz, 1H), 7.36 (dd, J=8.7, 2.3 Hz, 1H), 6.11 (d, J=8.7 Hz,1H), 4.59 (s, 1H), 4.53 (dt, J=12.9, 6.5 Hz, 2H), 4.36 (dt, J=31.2, 5.3Hz, 2H), 3.82 (p, J=5.9 Hz, 1H), 3.44 (s, 1H), 3.17 (s, 1H), 2.91 (s,1H), 2.87-2.73 (m, 1H), 2.75-2.64 (m, 1H), 1.94-1.78 (m, 1H), 1.73 (d,J=9.7 Hz, 1H).

Synthesis of 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane2,2,2-trifluoroacetate S31a). The title compound S31a was preparedaccording to the method presented for the synthesis of compound S1c butinstead utilizing tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylatefollowed by Boc deprotection in the same manner as the synthesis of thecompound S17b. MS (ESI) m/z 169.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 4.79 (t, J=6.9 Hz, 2H), 4.66 (dd, J=7.2, 5.2 Hz, 2H), 4.10 (tt, J=6.8,5.2 Hz, 1H), 3.76 (dq, J=5.0, 2.3 Hz, 2H), 3.51 (dd, J=13.6, 2.0 Hz,2H), 3.41-3.33 (m, 2H), 2.31-2.21 (m, 2H), 2.11-1.95 (m, 2H).

Synthesis of2-chloro-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridine(S31b). The title compound S31b was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizing2,6-dichloro-1,5-naphthyridine. MS (ESI) m/z 330.7 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 7.95 (dd, J=9.5, 0.8 Hz, 1H), 7.86 (dd, J=8.8, 0.8Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 4.71 (t, J=6.2Hz, 2H), 4.58 (t, J=5.7 Hz, 2H), 4.05 (d, J=11.3 Hz, 2H), 3.74-3.63 (m,1H), 3.28-3.20 (m, 5H), 1.86 (dd, J=9.1, 4.4 Hz, 2H).

Synthesis of2-ethynyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridine(S31). The title compound S31 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S31b.MS (ESI) m/z 321.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.93 (d,J=9.5 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.00 (d,J=9.5 Hz, 1H), 4.63 (t, J=6.2 Hz, 2H), 4.50 (t, J=5.8 Hz, 2H), 4.01 (d,J=11.8 Hz, 2H), 3.61 (p, J=6.0 Hz, 1H), 3.27-3.07 (m, 4H), 3.06 (s, 1H),1.77 (dd, J=8.9, 4.3 Hz, 2H), 1.66-1.52 (m, 2H).

Synthesis of3,3′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane)(S32a) The title compound S32a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizing S31aand 2,4,6-trichloro-1,3,5-triazine. MS (ESI) m/z 448.3 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) δ 4.70 (t, J=6.2 Hz, 4H), 4.56 (s, 3H), 4.32 (d,J=13.0 Hz, 2H), 4.30-4.20 (m, 2H), 3.64 (h, J=5.8 Hz, 2H), 3.21-3.04 (m,8H), 1.89-1.73 (m, 4H), 1.71-1.51 (m, 5H).

Synthesis of3,3′-(6-ethynyl-1,3,5-triazine-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane)(S32). The title compound S32 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S32a.MS (ESI) m/z 438.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 4.55 (t,J=6.2 Hz, 4H), 4.48-4.33 (m, 4H), 4.23 (d, J=12.5 Hz, 2H), 4.12 (t,J=10.9 Hz, 2H), 3.49 (q, J=5.7 Hz, 2H), 3.05-2.85 (m, 8H), 2.78 (s, 1H),1.71-1.57 (m, 4H), 1.52-1.34 (m, 4H).

Synthesis of3-(5-chloropyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S33a) The title compound S33a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing2,5-dichloropyrazine MS (ESI) m/z 281.3 [M+H]⁺. 1H NMR (400 MHz,Chloroform-d) δ 8.04 (d, J=1.4 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 4.72 (t,J=6.3 Hz, 2H), 4.58 (t, J=5.8 Hz, 2H), 3.77 (dd, J=11.6, 2.3 Hz, 2H),3.69 (ddd, J=11.9, 6.5, 5.5 Hz, 1H), 3.23 (dd, J=4.8, 2.6 Hz, 2H), 3.18(dd, J=11.5, 2.3 Hz, 2H), 1.92-1.83 (m, 2H), 1.73-1.65 (m, 2H).

Synthesis of3-(5-ethynylpyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S33) The title compound S33 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S33a.MS (ESI) m/z 271.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.21 (d,J=1.5 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 4.73 (dd, J=6.3 Hz, 2H), 4.59 (t,J=5.8 Hz, 2H), 3.90 (d, J=10.5 Hz, 1H), 3.70 (p, J=6.0 Hz, 1H),3.27-3.18 (m, 4H), 3.17 (s, 1H), 1.94-1.83 (m, 2H), 1.74-1.64 (m, 2H),1.57 (s, 1H).

Synthesis of tert-butyl6-(5-iodopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate(S34a) The title compound S34a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizingtert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. MS (ESI) m/z401.8 [M+H]⁺.

Synthesis of6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane(S34b). The title compound S34b was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing S34a.MS (ESI) m/z 272.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.22-8.09(m, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.7Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.87 (d, J=2.8Hz, 1H), 5.47 (d, J=2.7 Hz, 1H), 4.86-4.71 (m, 3H), 3.69-3.57 (m, 3H),3.53-3.44 (m, 3H), 3.10-3.03 (m, 3H), 2.96 (d, J=9.0 Hz, 2H), 2.02-1.95(m, 1H), 0.00 (s, 9H).

Synthesis of6-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane(S34). The title compound S34 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S34b.MS (ESI) m/z 256.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.32 (d,J=2.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.26 (d, J=8.6 Hz, 1H), 4.56 (t,J=6.8 Hz, 2H), 4.51-4.32 (m, 4H), 3.73 (s, 1H), 3.26-3.11 (m, 2H), 3.08(s, 1H), 3.00-2.85 (m, 2H), 2.71-2.58 (m, 1H), 2.21-1.98 (m, 1H).

Synthesis of tert-butyl3-(4-iodophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S35a). Thetitle compound S35aa was prepared according to the method presented forthe synthesis of compound S1c but instead utilizing 1,4-diiodobenzene.MS (ESI) m/z 414.9 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.56-7.43(m, 2H), 6.68-6.55 (m, 2H), 4.34 (s, 2H), 3.35 (dd, J=11.2, 2.4 Hz, 2H),2.97 (s, 2H), 2.00-1.80 (m, 4H), 1.46 (s, 9H).

Synthesis of3-(4-iodophenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35b).The title compound S35b was prepared according to the method presentedfor the synthesis of compound S1c but instead utilizing S35a. MS (ESI)m/z 371.2 [M+H]⁺.

Synthesis of3-(4-ethynylphenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35).The title compound S35 was prepared according to the method presentedfor the synthesis of compound S1 but instead utilizing S35b. MS (ESI)m/z 269.2 [M+H]⁺. H¹ NMR (400 MHz, Chloroform-d) δ 7.19-7.08 (m, 2H),6.53-6.40 (m, 2H), 4.49 (t, J=6.3 Hz, 2H), 4.36 (s, 2H), 3.50 (s, 1H),3.18 (dd, J=11.0, 2.5 Hz, 2H), 3.00 (s, 2H), 2.84 (d, J=10.7 Hz, 2H),2.75 (s, 1H), 1.72-1.47 (m, 4H).

Synthesis of tert-butyl3-(5-iodopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(S36a). The title compound S36a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizing2-chloro-5-iodopyrimidine. MS (ESI) m/z 416.8 [M+H]⁺.

Synthesis of 3-(5-ethynylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S36). The title compound S36 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S36a.MS (ESI) m/z 215.2 [M+H]⁺.

Synthesis of3-(5-iodopyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-9-one(S37a). The title compound S37a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one. MS (ESI) m/z 428.1[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.71 (s, 1H),6.62 (s, 1H), 4.70 (s, 2H), 4.37 (t, J=6.5 Hz, 2H), 4.15 (t, J=6.4 Hz,3H), 3.29-3.05 (m, 3H), 3.02-2.80 (m, 1H), 2.17 (dd, J=11.2, 2.3 Hz,2H), 1.55 (s, 2H), 1.03 (s, 6H).

Synthesis of3-(5-ethynylpyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-9-one(S37) The title compound S37 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S37a.MS (ESI) m/z 326.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.34 (d,J=2.2 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 4.80 (d,J=13.4 Hz, 2H), 4.34 (t, J=6.4 Hz, 2H), 4.12 (t, J=6.2 Hz, 2H),3.24-2.99 (m, 3H), 2.91 (d, J=10.9 Hz, 2H), 2.17 (dd, J=11.3, 2.3 Hz,2H), 1.55 (s, 1H), 1.03 (s, 6H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octane(S38). To a solution of S20a (630 mg, 1.76 mmol) in DCM (10 mL) wasadded N,N-diisopropylethylamine (1.22 ml, 0.01 mol), the mixture wascooled to 5° C., and then methanesulfonyl chloride (0.2 ml, 3.0 mmol)was added. After 3 min the reaction was quenched with NaHCO3 saturatedsolution, the organic layer was separated, dried over Na2SO4, filtered,concentrated and the residue was dissolved in MeOH (15 mL), the solutionwas cooled to 10° C., then added K2CO3 (0.44 g, 0.01 mol). After 15 minthe precipitate was filtered off, rinsed with 10% MeOH in water anddried under vacuum to give S38 (477 mg, 93.1%) MS (ESI) m/z 292.2[M+H]^(|). ¹H NMR (400 MHz, Chloroform-d) δ 8.07 (dd, J=2.3, 0.8 Hz,1H), 7.32 (dd, J=8.8, 2.3 Hz, 1H), 6.26 (d, J=8.8 Hz, 1H), 4.12 (dd,J=4.7, 2.4 Hz, 2H), 3.83 (dd, J=12.3, 2.5 Hz, 2H), 2.92 (dd, J=12.1, 2.1Hz, 2H), 2.84 (s, 1H), 2.75 (s, 3H), 1.89-1.76 (m, 2H), 1.65-1.56 (m,2H).

Synthesis of tert-butyl7-(5-iodopyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(S39a). The title compound S39a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizingtert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. MS (ESI) m/z430.2 [M+H]⁺.

Synthesis of3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonanedihydrochloride (S39b). The title compound S39b was prepared accordingto the method presented for the synthesis of compound S1 but insteadutilizing S39a. MS (ESI) m/z 300.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 7.97 (d, J=2.2 Hz, 1H), 7.74 (dd, J=9.4, 2.2 Hz, 1H), 7.10 (d, J=9.3Hz, 1H), 4.00 (d, J=12.6 Hz, 2H), 3.30 (d, J=13.0 Hz, 2H), 3.21 (t,J=11.5 Hz, 2H), 3.12 (d, J=13.0 Hz, 2H), 2.21 (s, 2H), 1.87 (d, J=13.8Hz, 1H), 1.78 (d, J=13.7 Hz, 1H), 0.00 (s, 9H).

Synthesis of1-(7-(5-ethynylpyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethan-1-one(S39). To a mixture of S39b (0.39 g, 1 mmol) and Et₃N (0.73 ml, 0.01mol) in DCM (10 mL), acetic anhydride (0.14 ml, 1 mmol) was added. After5 min, the reaction was quenched with 1M NaOH, the layers were separatedand the organic layer was dried over Na₂SO₄, filtered, concentrated andthe residue was dissolved in MeOH (20 mL), then added K₂CO₃ (0.44 g, 3mmol). After 20 min the reaction was diluted with DCM, washed withwater, the organic layer was dried over Na₂SO₄, filtered, concentratedunder reduced pressure and the residue was purified by silica columnchromatography (60%-100% EtOAc/hexanes to 5% MeOH/EtOAc) to give S39(111 mg, 39%) MS (ESI) m/z 270.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.12 (dd, J=2.3, 0.8 Hz, 1H), 7.48 (dd, J=9.0, 2.4 Hz, 1H), 6.69 (dd,J=9.0, 0.8 Hz, 1H), 4.74-4.59 (m, 2H), 4.33-4.20 (m, 1H), 4.04 (d,J=13.4 Hz, 1H), 3.42 (dt, J=13.5, 2.7 Hz, 1H), 3.39 (s, 1H), 3.11 (dddd,J=11.1, 8.0, 3.2, 2.2 Hz, 2H), 2.87 (dt, J=13.5, 2.6 Hz, 1H), 2.06 (q,J=3.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.84 (s, 3H).

Synthesis of3-(5-ethynylpyridin-2-yl)-7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane(S40). In a microwave tube a mixture of S39b (0.21 g, 0.6 mmol),2-Fluoropyridine (0.1 ml, 1 mmol), sodium bicarbonate (0.24 g, 3 mol) inNMP (1 mL) were microwaved at 130° C. for 20 min, then at 150° C. for 20min, the reaction was diluted with DCM, washed with water, the organiclayer was dried over Na₂SO₄, filtered, concentrated under reducedpressure and the residue was purified by silica column chromatography togive S40 (9 mg, 5%) MS (ESI) m/z 305.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.06 (d, J=2.3 Hz, 1H), 7.93 (dd, J=5.1, 2.0 Hz, 1H),7.25 (dd, J=9.0, 2.4 Hz, 1H), 7.25-7.16 (m, 1H), 6.39 (d, J=8.7 Hz, 1H),6.36-6.30 (m, 2H), 4.39-4.17 (m, 4H), 3.15-3.02 (m, 5H), 2.93 (s, 1H),2.18-2.07 (m, 2H), 1.89 (d, J=3.4 Hz, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonane(S41). The title compound S41 was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizing S39b.MS (ESI) m/z 284.3 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.17-7.96 (m,1H), 7.46 (dd, J=9.0, 2.4 Hz, 1H), 6.77-6.49 (m, 1H), 4.41 (t, J=6.4 Hz,2H), 4.26 (t, J=6.2 Hz, 2H), 4.19 (d, J=12.9 Hz, 2H), 3.31 (s, 1H),3.23-3.12 (m, 3H), 2.80-2.65 (m, 2H), 2.13-1.91 (m, 4H), 1.91-1.76 (m,1H), 1.73-1.61 (m, 1H).z

Synthesis of 3-(5-iodopyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(S43a). The title compound S43a was prepared according to the methodpresented for the synthesis of compound S1a but instead utilizing8-oxa-3-azabicyclo[3.2.1]octane. MS (ESI) m/z 317.1 [M+H]⁺.

Synthesis of 3-(5-ethynylpyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(S43b). The title compound S43 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S43a.MS (ESI) m/z 215.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.17 (dd,J=2.3, 0.8 Hz, 1H), 7.56 (dd, J=8.9, 2.3 Hz, 1H), 6.67 (dd, J=8.9, 0.8Hz, 1H), 4.46 (dq, J=4.4, 2.3 Hz, 2H), 3.86 (dt, J=12.8, 1.1 Hz, 2H),3.43 (s, 1H), 3.07 (d, J=2.6 Hz, 1H), 3.03 (d, J=2.6 Hz, 1H), 2.02-1.74(m, 4H).

Synthesis of3-(3-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S44a) The title compound S44a was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing2-fluoro-5-iodo-3-methylpyridine. MS (ESI) m/z 300.3 [M+H]⁺.

Synthesis of3-(5-ethynyl-3-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S44). The title compound S44 was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing S44a.MS (ESI) m/z 284.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.24 (d,J=2.2 Hz, 1H), 8.05 (d, J=2.3 Hz, 0H), 7.43 (dd, J=2.1, 0.9 Hz, 1H),7.30 (d, J=1.9 Hz, 0H), 7.19 (d, J=15.2 Hz, 0H), 5.80 (d, J=15.1 Hz,0H), 5.30 (s, 0H), 4.70 (t, J=6.2 Hz, 3H), 4.59 (s, 2H), 3.76 (s, 1H),3.35-3.26 (m, 2H), 3.18 (d, J=30.6 Hz, 5H), 3.09 (s, 1H), 2.27 (s, 0H),2.24 (s, 3H), 1.96-1.79 (m, 5H), 0.24 (d, J=7.3 Hz, 0H), 0.15 (d, J=6.0Hz, 0H), 0.08 (s, 0H).

Synthesis of3-(6-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S45a) The title compound S45a was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing6-fluoro-3-iodo-2-methylpyridine. MS (ESI) m/z 300.3 [M+H]⁺.

Synthesis of3-(5-ethynyl-6-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S45). The title compound S45 was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing S45a.MS (ESI) m/z 284.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.46 (d,J=8.7 Hz, 1H), 6.28 (d, J=8.7 Hz, 1H), 5.30 (s, 0H), 4.72 (t, J=6.3 Hz,2H), 4.59 (t, J=5.8 Hz, 2H), 4.07 (d, J=12.6 Hz, 0H), 3.89 (d, J=11.0Hz, 2H), 3.71 (p, J=6.0 Hz, 1H), 3.26 (d, J=13.4 Hz, 1H), 3.24 (s, 0H),3.23 (s, 1H), 3.19 (s, 2H), 3.14-3.07 (m, 2H), 2.51 (s, 3H), 1.85 (dd,J=11.5, 6.7 Hz, 2H), 1.70 (t, J=6.7 Hz, 1H).

Synthesis of3-(4-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S46a) The title compound S46a was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing2-fluoro-5-iodo-4-methylpyridine. MS (ESI) m/z 300.4 [M+H]⁺.

Synthesis of3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane(S46). The title compound S46 was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing S46a.MS (ESI) m/z 284.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.22 (s,1H), 6.33 (s, 1H), 5.30 (s, 0H), 4.72 (t, J=6.3 Hz, 2H), 4.59 (t, J=5.8Hz, 2H), 3.85 (dd, J=11.8, 2.4 Hz, 2H), 3.70 (p, J=6.0 Hz, 1H), 3.24 (s,0H), 3.23 (s, 1H), 3.22-3.09 (m, 4H), 2.34 (d, J=0.7 Hz, 3H), 1.85 (dd,J=8.9, 4.3 Hz, 2H), 1.72-1.66 (m, 2H).

Synthesis of 4-(5-iodopyridin-2-yl)-1-methylpiperazin-2-one (S47a). Thetitle compound S47a was prepared according to the methods presented forthe synthesis of compound S1a but instead utilizing1-Methylpiperazin-2-one hydrochloride. MS (ESI) m/z 318.0 [M+H]⁺.

Synthesis of3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane4-(5-ethynylpyridin-2-yl)-1-methylpiperazin-2-one (S47). The titlecompound S47 was prepared according to the methods presented for thesynthesis of compound S3 but instead utilizing S47a. MS (ESI) m/z 216.1[M+H]⁺.

Synthesis of 1-(5-ethynylpyridin-2-yl)-4-(oxetan-3-yl)piperazine (S48).The title compound S48 was prepared according to the methods presentedfor the synthesis of compound S1 but instead utilizing 1-(oxetan-3-yl)piperazine. MS (ESI) m/z 244.16 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.18 (d, J=2.2 Hz, 1H), 7.56 (dd, J=8.9, 2.3 Hz, 1H), 6.75 (d, J=8.9 Hz,1H), 4.70 (t, J=6.6 Hz, 3H), 4.63 (t, J=6.2 Hz, 3H), 3.68-3.56 (m, 6H),3.55-3.47 (m, 1H), 3.42 (s, 1H), 2.52-2.37 (m, 6H), 1.27 (d, J=13.9 Hz,0H).

Synthesis of 5-ethynyl-2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidine(S49). The title compound S49 was prepared according to the methodspresented for the synthesis of compound S1 but instead utilizingtert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate. MS (ESI)m/z 245.2 [M+H]⁺.

Synthesis of5-ethynyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine(S50). The title compound S50 was prepared according to the methodspresented for the synthesis of compound S1 but instead utilizingtert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate and4-Oxotetrahydropyran. MS (ESI) m/z 272.70 [M+H]⁺.

Synthesis of tert-butyl3-((3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)azetidine-1-carboxylate(S51). The title compound S51 was prepared according to the methodspresented for the synthesis of compound S1 but instead utilizing S3b andtert-butyl 3-formylazetidine-1-carboxylate. MS (ESI) m/z 383.05 [M+H]⁺.

Synthesis of3-(5-iodopyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane(S52a) The title compound S52a was prepared according to the methodpresented for the synthesis of compound S1c but instead utilizingtert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and2-chloro-5-iodopyrimidine. MS (ESI) m/z 359.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.47 (s, 2H), 4.70 (t, J=6.2 Hz, 2H), 4.48 (t, J=5.5 Hz,2H), 3.87 (p, J=5.5 Hz, 1H), 3.81 (d, J=6.1 Hz, 2H), 3.56 (q, J=13.2 Hz,4H), 2.74 (q, J=7.8 Hz, 1H), 1.58 (d, J=8.9 Hz, 1H).

Synthesis of3-(5-ethynylpyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane(S52) The title compound S52 was prepared according to the methodpresented for the synthesis of compound S1 but instead utilizing S52a.MS (ESI) m/z 257.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.32 (s,2H), 4.55 (t, J=6.1 Hz, 2H), 4.32 (dd, J=6.0, 4.8 Hz, 2H), 3.72 (ddd,J=11.1, 6.2, 4.9 Hz, 1H), 3.65 (d, J=6.0 Hz, 2H), 3.50 (d, J=13.3 Hz,2H), 3.43 (d, J=13.3 Hz, 2H), 3.06 (s, 1H), 2.58 (dt, J=8.1, 6.1 Hz,1H), 1.44 (d, J=8.8 Hz, 1H).

Synthesis of(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)boronicacid (S53) A suspension of S4a (0.17 g, 0.47 mmol) Bis (Pinacolato)Diboron (0.18 g, 0.72 mmol), potassium acetate (0.17 g, 1.68 mmol) and[1,1′bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.04 g,0.05 mmol) in DMF (4.5 mL) was degassed with argon for 5 min, thenheated at 90° C. for 1 h. Cooled to room temperature, Diluted with EtOAcand washed with 5% LiCL solution 2×. The separated organic layer wasdried over Na₂SO₄ and concentrated under vacuum, the residue waspurified by HPLC and the product was lyophilized to afford S53. MS (ESI)m/z 276.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J=1.7 Hz,1H), 8.31 (dd, J=9.0, 1.8 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.74-4.58 (m,4H), 4.27-3.99 (m, 4H), 3.28-3.16 (m, 1H), 2.21-2.06 (m, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-methyl-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-iumiodide (S54 and S55). To a solution of S3 in acetone (1 mL) in a vial at30° C. was added Iodomethane (0.06 ml, 1.0 mmol), warmed up to 70° C.and the mixture was stirred overnight. After cooling to room temperaturethe reaction was diluted with ether, stirred for 5 min, the solids werefiltered and dried in vacuum to afford a 3:1 mixture of isomers (S54:S55) where the major product (S4) has the methyl syn to the bridge. MS(ESI) m/z 284.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.08-8.02 (m,1H), 7.50-7.40 (m, 1H), 6.58 (d, J=9.0 Hz, 0H), 6.54 (dd, J=8.8, 0.9 Hz,1H), 5.37 (t, J=8.1 Hz, 1H), 4.86-4.70 (m, 5H), 4.05-3.94 (m, 3H), 3.88(d, J=14.3 Hz, 3H), 3.54 (d, J=14.7 Hz, 1H), 3.45 (s, 1H), 3.37 (d,J=2.1 Hz, 1H), 3.34 (s, 4H), 3.30 (s, 1H), 2.37-2.27 (m, 2H), 2.21-2.11(m, 1H), 2.07-1.94 (m, 2H), 1.94 (s, 1H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane(S56). The title compound S56 was prepared according to the methodspresented for the synthesis of compound S1 but instead utilizing3-(5-iodopyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane.MS (ESI) m/z 298.19 [M+H]^(|).

Synthesis of1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S57). Thetitle compound S57 was prepared according to the methods presented forthe synthesis of compound S50 but instead utilizingdihydrofuran-3(2H)-one. ¹H-NMR and MS data identical to S14.

Synthesis of 4-(5-ethynylpyrimidin-2-yl)piperazin-2-one (S58a). Thetitle compound S58a was prepared according to the methods presented forthe synthesis of compound S47 but instead utilizing piperazin-2-one and2-chloro-5-iodopyrimidine MS (ESI) m/z 303.0 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.44 (s, 2H), 6.11 (s, 1H), 4.46 (s, 2H), 4.16-3.91 (m,2H), 3.47 (td, J=5.4, 2.7 Hz, 2H), 3.19 (s, 1H).

Synthesis of 4-(5-ethynylpyrimidin-2-yl)-1-methylpiperazin-2-one (S58).To a solution of S58a (115 mg, 0.57 mmol) in THF (5 mL) and DMF (1 mL)at 0° C. was added sodium hydride, (60% oil dispersion, 59 mg, 1.475mmol). After 15 min, added iodomethane (0.15 ml, 2.409 mmol). Thereaction mixture was warmed up to room temperature and stirred for 2 h,then quenched with water and partitioned with EtOAc. The separatedorganic layer was dried over Na₂SO₄ and concentrated under vacuum toafford S58 (124.9 mg, 100%). MS (ESI) m/z 217.1 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d4) δ 8.45 (s, 2H), 4.37 (s, 2H), 4.18-4.03 (m, 2H), 3.65 (s,1H), 3.57-3.43 (m, 2H), 3.01 (s, 3H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane(S59). The title compound S59 was prepared according to the methodspresented for the synthesis of compound S3 but instead utilizing2-methoxyacetaldehyde. MS (ESI) m/z 303.02 [M+H]⁺.

Synthesis of(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)boronicacid (S60). The title compound S60 was prepared according to the methodspresented for the synthesis of compound S53 but instead utilizing S3c.MS (ESI) m/z 290.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H),8.08 (d, J=9.2 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H), 4.91 (t, J=7.3 Hz, 3H),4.76 (dd, J=7.7, 5.2 Hz, 2H), 4.36 (s, 1H), 4.17 (d, J=13.4 Hz, 3H),4.00 (s, 2H), 3.46 (d, J=13.2 Hz, 2H), 2.28-2.10 (m, 2H), 2.01 (d, J=8.4Hz, 2H).

Synthesis of3-(5-ethynylpyridin-2-yl)-8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S61). A suspension of S20a (0.15 g, 0.42 mmol), sodium bicarbonate (250mg, 2.9 mmol), and 2-Chloropyrimidine (0.17 g, 1.5 mmol) in isopropanol(1.5 mL) was stirred at 65° C. overnight. The reaction mixture was thencooled to room temperature, diluted with ethyl acetate and filteredthrough celite. The crude mixture was concentrated in vacuo andredissolved in methanol (5 mL). Potassium carbonate (0.29 g, 2.1 mmol)was added and the mixture was stirred for 30 minutes. The reaction wasquenched with water and the crude product was extracted into DCM, driedover sodium sulfate, filtered, concentrated in vacuo, and purified bycolumn chromatography (30% →70% EtOAc→hexanes). MS (ESI) m/z 292.2[M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J=4.8 Hz, 2H), 8.17(dd, J=2.4, 0.8 Hz, 1H), 7.55 (dd, J=8.9, 2.3 Hz, 1H), 6.69 (dd, J=9.0,0.8 Hz, 1H), 6.64 (t, J=4.8 Hz, 1H), 4.89 (dq, J=4.6, 2.3 Hz, 3H), 4.02(dd, J=12.4, 2.3 Hz, 3H), 3.42 (s, 1H), 3.13 (dd, J=12.3, 2.3 Hz, 3H),2.08-1.96 (m, 3H), 1.96-1.82 (m, 3H).

3-(5-ethynylpyridin-2-yl)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane(S62). The title compound S62 was prepared according to the methodspresented for the synthesis of compound S63 but instead utilizing2,2,2-Trifluoroethyl trifluoromethanesulfonate. MS (ESI) m/z 296.20[M+H]⁺.

Synthesis of8-(2,2-difluoroethyl)-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane(S63). To a suspension of Reactant 1 (0.2 g, 0.56 mmol) and2-Iodo-1,1-difluoroethane (0.15 g, 0.78 mmol) in 1,4-Dioxane (3 ml) wereadded Cesium carbonate 99.95% (0.21 g, 3.35 mmol). The mixture wasstirred at 60° C. overnight. Cooled to room temperature and2,2-Difluoroethyl trifluoromethane sulfonate(98% min) (0.17 g, 0.78mmol) was added. The mixture was warmed up to 60° C. for 8 h. Quenchedwith brine, extracted with EtOAc. The organic layer was dried overNa2SO4, filtered, concentrated and purified by silica columnchromatography (10% EtOAc/Hex). The product was dissolved in Methanol (3ml), potassium carbonate (0.11 g, 0.82 mmol) was added and after 1 h themixture was concentrated diluted with EtOAc, washed with water, driedover Na2SO4, filtered concentrated to yield S63 (76 mg, 99.7%). MS (ESI)m/z 278.2 [M+H]⁺

Synthesis(3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(3-methyloxetan-3-yl)methanone(S64) To S20a suspended in CH₂Cl₂ (10 mL) was added3-methyloxetane-3-carboxylic acid (0.12 g, 1 mmol), Et₃N (0.68 ml, 5mmol) followed by HATU (0.48 g, 1 mmol). The mixture was stirred for 1.5h. The mixture was diluted with DCM and washed with water. The organiclayer was dried over Na₂SO₄, and concentrated in vacuo. The residue wasdissolved in MeOH (20 mL), cooled to 5° C. and potassium carbonate (0.4g, 3 mmol) was added. After 30 min, the reaction quenched with water andbrine, extracted into DCM, dried over Na₂SO₄, filtered, concentratedunder reduced pressure and the residue was purified by silica columnchromatography (60%-100% EtOAc/hexanes to 5% MeOH/EtOAc) to give S64. MS(ESI) m/z 312.22 [M+H].

2.3 Synthesis of A Intermediates

Synthesis of ethyl 2-(1,1,1-trifluoropropan-2-ylidene)malonate (A1a) Amixture of dry THF (5000 mL) and dry CCl₄ (600 mL) was cooled to 0° C.and treated with TiCl₄ (275 mL, 2.50 mol). The resulting yellowsuspension was stirred at 0° C. for 5 min, treated sequentially with1,1,1-trifluoropropan-2-one (140 g, 1.25 mol) and freshly distilleddiethyl malonate (200 g, 1.25 mol), and then stirred at 0° C. for 0.5hour. The reaction mixture was then treated with a solution of drypyridine (400 mL) in dry THF (500 mL) and stirred at 0° C. for 1 hourand then at room temperature overnight. The reaction mixture wasquenched with water and extracted with EtOAc (1 L×3). The combinedorganic extracts were washed with brine and saturated NaHCO₃, dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (EtOAc:PE=1:50) togive the title compound A1a (298 g, 94%).

¹H NMR (CDCl₃, 300 MHz): δ 4.32-4.23 (m, 4H), 2.20 (s, 3H), 1.33-1.24(m, 6H).

Synthesis of diethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)malonate(A1b) A mixture of methylmagnesium iodide (3.0 mol/L in ether, 10 L, 30mol) and cuprous chloride (3.5 g, 35 mmol) was stirred at 0° C., treatedwith a solution of compound A1a (178 g, 700 mmol) in dry Et₂O (1000 mL)over 30 min, and stirred at rt for 30 min and then quenched with thedropwise addition of ice-water (1.5 L) followed by HCl aq (3 mol/L, 350mL). The mixture was then extracted with Et₂O (1 L×3). The combinedorganic extracts were washed with NaOH aq (1 N), water and brine, dried(MgSO₄), filtered and evaporated. The residue crude compound A1b (90 g,47%) was used directly in next step without further purification. MS(ESI) m/z 271 [M+H]⁺. ¹H NMR (CDCl₃, 300 MHz): δ 4.22-4.15 (m, 4H), 3.64(s, 1H), 1.38 (s, 6H), 1.30-1.24 (m, 6H).

Synthesis of 2-(ethoxycarbonyl)-4,4,4-trifluoro-3,3-dimethylbutanoicacid (A1e) A solution of compound A1b (144 g, 0.53 mol) in a mixture ofEtOH (500 mL) and water (500 mL) was treated with NaOH (19 g, 0.48 mmol)in portions at 0° C., and stirred at room temperature for 5 hours. Thereaction mixture was evaporated to syrup, dissolved in water (1 L), andextracted with Et₂O (2 L). The aqueous phase was acidified with 1 M HClto pH=2.0 and extracted with EtOAc (1 L×3). The combined organicextracts were washed with brine, dried (MgSO₄), filtered and evaporatedto give the title compound A1e (107 g, 84%) which was used directly innext step without further purification. MS (ESI) m/z 241 [M+H]⁺. ¹H NMR(CDCl₃, 300 MHz): δ 4.23 (q, J=5.4 Hz, 2H), 3.69 (s, 1H), 1.40 (s, 6H),1.27 (t, J=5.1 Hz, 3H).

Synthesis of ethyl2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoate(A1d) A solution of compound A1e (110 g, 454 mmol) in dry toluene (600mL) was treated with triethylamine (45.4 g, 454 mmol) anddiphenylphosphoryl azide (125 g, 454 mmol), the reaction mixture wasrefluxed for 1 hour, then t-BuOH (46.7 g, 630 mmol) was added in. Themixture was refluxed overnight. Cooled to rt, the solvent was evaporatedand the residue was dissolved in EtOAc (1 L), washed with 5% NaHCO₃solution, dried (MgSO₄), filtered and evaporated. The remainder waspurified by column chromatography on silica gel (EtOAc:PE=1:9) to givecrude compound A1d (60 g, 46%), which was used directly in next stepwithout further purification. MS (ESI) m/z 313 [M+H]⁺. ¹H NMR (CDCl₃,300 MHz): δ 5.20 (d, J=5.7 Hz, 1H), 4.44 (d, J=10.8 Hz, 1H), 4.25-4.16(m, 2H), 1.44 (s, 9H), 1.39-1.26 (m, 6H), 1.19 (m, 3H).

Synthesis of2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid(A1e) To a solution of compound A1d (380 g, 1214 mmol) in water (2000mL) and ethanol (2000 mL) was added LiOH.H₂O (134 g, 3166 mmol). Themixture was stirred overnight. Diluted with EtOAc, acidify to pH=2,extracted with EtOAc (2000 mL×3). The organic layer was washed withbrine, dried over MgSO₄, and concentrated to afford compound A1e (300 g,86%) as a white solid. ¹H NMR (CDCl₃, 300 MHz): δ 5.20 (d, J=10.2 Hz,1H), 4.48 (d, J=10.2 Hz, 1H), 1.45 (s, 9H), 1.30 (s, 3H), 1.25 (s, 3H).

Synthesis of (S)-(S)-1-phenylethyl2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-dimethylbutanoate (A1g)The acid A1e (300 g, 1052 mmol) and (N,N′-Dicyclohexylcarbodiimide (325g, 1578 mmol) were combined in DCM (250 mL) and PhMe (4000 mL). Thesolution was cooled to 0° C., and then 4-(Dimethylamino)pyridine (128 g,1052 mmol) and (S)-(-)-1-Phenylethanol (128 g, 1052 mmol) were added andthe mixture was allowed to warm to room temperature and stirredovernight. The mixture was concentrated, and then the residue was takenup in EtOAc/water, and extracted with EtOAc (2000 mL×3). The combinedorganic layers were washed with brine, dried over MgSO₄ andconcentrated. The crude was purified by column chromatography on silicagel (0-8% EtOAc/PE) to get two compounds. The mixture of diastereomerswas separated by chiral column (IA; Heptane;IPA (70:30)). First peak wascollected to get the compound A1f (105 g, 25%) and the second peak wascollected to get the compound A1g (80 g, 19%). ¹H NMR of compound A1f(CDCl₃, 300 MHz): δ 7.38-7.31 (m, 5H), 5.90 (q, J=6.3 Hz, 1H), 5.18 (d,J=9.6 Hz, 1H), 4.48 (d, J=9.6 Hz, 1H), 1.56 (d, J=6.9 Hz, 3H), 1.44 (s,9H), 1.31 (s, 3H), 1.21 (s, 3H). ¹H NMR of compound A1g (CDCl₃, 300MHz): δ 7.34-7.30 (m, 5H), 5.92 (q, J=6.3 Hz, 1H), 5.20 (d, J=9.6 Hz,1H), 4.44 (d, J=9.6 Hz, 1H), 1.58 (d, J=6.9 Hz, 3H), 1.45 (s, 9H), 1.21(s, 3H), 1.11 (s, 3H).

Synthesis of(S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoicacid (A1) The compound A1f (83 g, 214 mmol) was diluted with ethanol(1000 mL). Pd/C (10%, wet, 17 g) was added and the atmosphere wasreplaced with hydrogen. After stirring for 5 hours, the mixture wasfiltered over celite, washing with EtOAc and the filtrate wasconcentrated to get product A1 (50 g, 82%). MS (ESI) m/z 186 [M-Boc+1]⁺.¹H NMR (300 MHz, DMSO-d₆): δ 12.98 (br s, 1H), 7.18 (d, J=9.6 Hz, 1H),4.27 (d, J=9.9 Hz, 1H), 1.36 (s, 9H), 1.14 (s, 6H).

Synthesis of(R)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoicacid (A2) The compound A1g (80 g, 205 mmol) was diluted with ethanol(800 mL). Pd/C (10%, wet, 15 g) was added and the atmosphere wasreplaced with hydrogen. After stirring for 5 hours, the mixture wasfiltered over celite, washing with EtOAc and the filtrate wasconcentrated to get product A2 (45 g, 77%). MS (ESI) m/z 186 [M-Boc+1]⁺.¹H NMR (300 MHz, DMSO-d₆): δ 7.18 (d, J=9.6 Hz, 1H), 4.25 (d, J=9.9 Hz,1H), 1.36 (s, 9H), 1.14 (s, 6H).

Synthesis of (S)-4, 4, 4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A3) To a solution of A1 (10 g, 35.06 mmol) inDCM (160 mL) and MeOH (40 mL), was added HCl (4.0M in dioxane, 40 mL).The reaction was stirred at room temperature overnight. The reaction wasconcentrated to dryness (foamy). The residue was dissolved in a mixtureof dioxane and 2M NaOH (90 mL), stirred for 5 min, and then add methylchloroformate (5.7 mL, 73.33 mmol). After 4 h the reaction was extractedwith 2×100 mL DCM (discard organics) and the aqueous layer was adjustedto pH ˜2 with 4M HCl (˜50 mL). The aqueous layer was extracted with2×150 mL EtOAc, the combined EtOAc layers were dried over sodiumsulfate, filtered, and concentrated to give A3 (8.54 g, 100%). MS (ESI)m/z 244.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 4.57-4.41 (m, 1H),3.66 (d, J=2.1 Hz, 5H), 1.25 (d, J=10.0 Hz, 7H).

Synthesis of(S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanoicacid (A4). The title compound A4 was prepared according to the methodpresented for the synthesis of compound A3 but instead utilizing4-nitrophenyl oxetan-3-yl carbonate. MS (ESI) m/z 285.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 7.66 (d, J=9.9 Hz, 1H), 5.37 (tt, J=6.3, 5.1Hz, 1H), 4.87-4.82 (m, 2H), 4.62 (tdd, J=7.5, 5.1, 0.9 Hz, 2H),4.49-4.41 (m, 1H), 1.28 (s, 3H), 1.25 (s, 3H).

Synthesis of (S)-2-((cyclopropoxycarbonyl) amino)-3, 3-dimethylbutanoicacid (A5) To a solution of cyclopropanol (0.4 ml, 6.37 mmol) in CH₃CN(18 mL) at 0° C., was added bis(2,5-dioxopyrrolidin-1-yl) carbonate(DSC) (3.26 g, 12.74 mmol) followed by Et₃N (2.66 ml, 19.11 mmol). Thereaction mixture was warmed up to 40° C. and stirred overnight. Aftercooling to room temperature, the reaction was concentrated under reducedpressure and the residue triturated with DCM, the solid filtered, andthe filtrated was purified by silica column chromatography (10%-100%EtOAc/hexanes). The product (663 mg, 3.33 mmol) was dissolved in THF (5mL) and L-tert-leucine methyl ester hydrochloride (0.91 g, 5 mmol) andEt₃N (1.39 ml, 0.01 mol) were added, the reaction was warmed up to 40°C. for 18h, then at room temperature for 48 h, diluted with EtOAc,washed with water. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure and the residue (760 mg, 3.31 mmol)was dissolved in a mixture of Methanol (4 mL)/water (2 mL), lithiumhydroxide, monohydrate (0.56 g, 0.01 mol) was added. After 16 h, themixture was concentrated, diluted with EtOAc, washed with brine, theorganic layer was dried over Na2SO4, filtered, and concentrated underreduced pressure to afford A5 ¹H NMR (400 MHz, Chloroform-d) δ 4.19 (d,J=9.6 Hz, 1H), 1.02 (s, 11H), 0.68 (d, J=4.8 Hz, 5H).

Synthesis of(S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoicacid (A6) The title compound A6 was prepared according to the methodpresented for the synthesis of compound A3 but instead utilizingcyclopropyl (2,5-dioxopyrrolidin-1-yl) carbonate. 1H NMR (400 MHz,Chloroform-d) δ 5.33 (d, J=9.8 Hz, 1H), 4.53 (d, J=9.9 Hz, 1H),4.08-4.01 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 0.81-0.52 (m, 4H).

Synthesis of(S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A7)The title compound A7 was prepared according to the method presented forthe synthesis of compound A3 but instead utilizing(S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutanoic acid(US 2013/0183629 A1 (pp. 178-179))

Synthesis of(S)-2-((methoxycarbonyl)amino)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)aceticacid (A8). The title compound A8 was prepared according to the methodpresented for the synthesis of compound A3 but instead utilizing(S)-2-amino-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid.MS (ESI) m/z 267.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 4.35-4.26 (m,1H), 3.65 (s, 3H), 1.97 (qd, J=9.6, 1.7 Hz, 6H).

2.4 Synthesis of I Intermediates

Synthesis of tert-butyl((2S,3S)-4-hydrazinyl-3-hydroxy-1-(4-iodophenyl)butan-2-yl) carbamate(I1a). To a solution of the NH₂NH₂ (48.3 g, 0.82 mol) in iPrOH (157 mL)was added tert-butyl((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (16.1 g, 41.4mmol) dissolved in DCM (79 mL) dropwise over 1 h at 0° C. The ice bathwas removed and the reaction mixture was stirred at rt for 16 h. Themixture was evaporated solvents, diluted with water, filtrated, washedwith water and dried to give compound I1a (17.0 g, 97%). ¹H NMR (300MHz, CDCl₃): δ 7.59 (d, J=7.8 Hz, 2H), 7.02-6.96 (m, 2H), 5.03 (d, J=9.9Hz, 1H), 3.78-3.66 (m, 2H), 2.85-2.67 (m, 4H), 2.04 (s, 3H), 1.38 (s,9H).

Synthesis of((S)-1-{(1S,2S)-2-hydroxy-1-(4-iodo-benzyl)-3-[N′-((S)-2-methoxycarbonylamino-3,3-dimethyl-butyryl)-hydrazino]-propylcarbamoyl}-2,2-dimethyl-propyl)-carbamicacid methyl ester (I1). To a solution of the I1a (34.0 g, 80.7 mmol) inCH₂Cl₂ (990 mL) at room temperature was added 4 M hydrochloric acid (198mL). After stirring for 2 h at 45° C., LC/MS indicated completion of thereaction and the mixture was concentrated in vacuo. To this cruderesidue suspended in CH₂Cl₂ (700 mL) and cooled to −20° C. was addedDIPEA (48.2 g, 373.9 mmol), Moc-tBu-Gly (25.53 g, 135.1 mmol) followedby HATU (53.4 g, 140.5 mmol). The mixture was warmed up to roomtemperature slowly and stirred for 1 h. The mixture was diluted with DCM(1 L) and washed with aqueous 1N HCl solution (400 mL), aqueoussaturated NaHCO₃ solution (400 mL), water (600 mL×2), and brine (600 mL)in sequence. The organic layer was dried over Na₂SO₄, and concentratedin vacuo to give the residue which was purified by column chromatographyon silica gel eluted with EtOAc: petroleum ether=2:1 to 100% of EtOAc toEtOAc: MeOH=50: 1 to give product I1 (8.2 g, 19.4%). MS (ESI) m/z 664.0[M+H]⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.53 (d, J=8.1 Hz, 2H), 7.01 (d,J=8.4 Hz, 2H), 4.10-4.21 (m, 1H), 3.90 (s, 1H), 3.82 (s, 1H), 3.69-3.64(m, 7H), 2.78-2.76 (m, 4H), 0.95 (s, 9H), 0.91 (s, 9H);

Synthesis of tert-butyl2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4iodophenyl)butyl)hydrazine-1-carboxylate (I2a) A mixture of tert-butyl((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (5 g, 12.85mmol) and tert-butylhydrazinecarboxylate (3.4 g, 25.69 mmol) inisopropanol (60 mL) was heated to 80° C. for 48h, then cooled to roomtemperature and concentrated under reduced pressure. The residue waspurified by silica column chromatography (0% to 40% EtOAc/DCM) to affordI2a (4.86 g, 72.6%) MS (ESI) m/z 522.19 [M+H]⁺

Synthesis of methyl((5S,10S,11S,14S)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(I2) I2a (5.0 g, 10 mmol) was dissolved in DCM (15 mL) and HCl (4.0M indioxane, 36 mL). The reaction was stirred overnight then concentratedunder reduce pressure. To the residue was added A3 (4.96 g, 20 mmol) andHATU (8.02 g, 21 mmol) in DCM (100 mL), followed byN,N-diisopropylethylamine (16.7 ml, 96 mmol). The reaction was stirredat stirred at room temperature overnight. The reaction mixture wasdiluted with DCM and washed with saturated NaHCO3, and brine then driedover Na₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (2% to 5% MeOH/DCM)to afford I2 (7.39 g, 60%) MS (ESI) m/z 773.0 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d4) δ 7.52 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 3.71 (q,J=6.9 Hz, 7H), 3.65 (s, 3H), 1.37 (dd, J=7.0, 1.7 Hz, 32H), 1.19-1.07(m, 10H).

Synthesis of tert-butyl((2S,3S)-3-hydroxy-1-(4-iodophenyl)-4-(2((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)butan-2-yl)carbamate(I3a). The title compound I3a was prepared according to the methodpresented for the synthesis of compound I1 but instead utilizing methyl(S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate. MS (ESI) m/z593.1 [M+H]⁺.

Synthesis of methyl((5S,10S,11S,14S)-5-(tert-butyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamateThe title compound I3 was prepared according to the method presented forthe synthesis of compound I2 but instead utilizing I3a and A3. MS (ESI)m/z 718.7 [M+H]⁺.

Synthesis of(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoicacid (I4a) L-tert-Leucine (2 g, 15.25 mmol) was dissolved in 10% Na₂CO₃solution (80 ml), the solution was cooled to 0° C., then added9-Fluorenylmethyl chloroformate (4.77 g, 18.44 mmol) in dioxane (31 mL).After 2 h, the reaction mixture was diluted with water, washed withether and the aqueous layer was adjusted to pH ˜2 with 6N HCl andextracted with EtOAc. The combined EtOAc layers were dried over Na₂SO₄,filtered, and concentrated to give I4a. MS (ESI) m/z 353.8 [M+H]⁺.

Synthesis of (9H-fluoren-9-yl)methyl((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I4)

To I4a (2.55 g, 7.22 mmol) was added I1a (3 g, 7.12 mmol), HATU (2.7 g,7.1 mmol) and a mixture of CH₂Cl₂/DMF (2:1) (75 ml) followed byN,N-diisopropylethylamine (3 ml, 17.22 mmol). The reaction was stirredat stirred at room temperature for 4 h. The reaction mixture was dilutedwith EtOAc and washed with saturated NH₄Cl, and brine then dried overNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (2% to 5% MeOH/DCM)to afford I4 (2.38 g, 44%) MS (ESI) m/z 757.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 8.01 (s, 1H), 7.75 (t, J=7.5 Hz, 5H), 7.66-7.46 (m, 6H),7.38 (q, J=7.5 Hz, 4H), 7.34-7.27 (m, 1H), 6.95 (dd, J=16.8, 8.0 Hz,4H), 5.52 (d, J=47.2 Hz, 2H), 5.01 (dd, J=19.2, 10.0 Hz, 1H), 4.48 (dd,J=10.5, 6.5 Hz, 1H), 4.34 (dt, J=28.9, 9.8 Hz, 2H), 4.19 (t, J=6.8 Hz,2H), 3.91 (dd, J=45.4, 14.8 Hz, 2H), 3.60 (d, J=31.0 Hz, 2H), 1.39 (d,J=16.0 Hz, 13H).

Synthesis of tert-butyl((2S,3S)-4-(2-((S)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-1-(4-iodophenyl)butan-2-yl)carbamate(I5) The title compound I5 was prepared according to the methodpresented for the synthesis of compound I2 but instead utilizing I4 andA5. MS (ESI) m/z 619.4 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.02 (s,0H), 7.59 (d, J=8.0 Hz, 2H), 7.00 (d, J=7.9 Hz, 2H), 5.37 (s, 1H), 5.04(s, 1H), 4.02 (s, 1H), 3.83 (s, 1H), 3.74-3.58 (m, 1H), 2.95 (s, 1H),2.88 (d, J=0.7 Hz, 1H), 2.85 (d, J=7.7 Hz, 1H), 2.80 (s, 6H), 1.38 (s,8H), 1.01 (d, J=10.5 Hz, 1H), 0.90 (s, 8H), 0.66 (d, J=4.7 Hz, 4H).

Synthesis of tert-butyl((2S,3S)-4-(2-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-1-(4-iodophenyl)butan-2-yl)carbamate(I6a). The title compound I6a was prepared according to the methodpresented for the synthesis of compound I4 but instead utilizing A7. MS(ESI) m/z 611.5 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=8.0Hz, 2H), 6.98 (d, J=8.1 Hz, 2H), 5.50 (s, 1H), 4.97 (d, J=9.8 Hz, 1H),4.37-4.17 (m, 1H), 4.03 (td, J=25.3, 23.8, 9.4 Hz, 2H), 3.68 (s, 4H),3.50 (s, 0H), 3.17 (qd, J=7.4, 4.4 Hz, 1H), 2.94 (s, 1H), 2.82 (dt,J=15.8, 5.5 Hz, 4H), 1.50 (t, J=7.4 Hz, 1H), 1.46 (dd, J=17.4, 6.7 Hz,3H), 1.39 (s, 9H), 0.96 (s, 5H).

Synthesis of methyl((5S,8S,9S,14S)-16-fluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(16). The title compound I6 was prepared according to the methodpresented for the synthesis of compound I2 but instead utilizing I6a. MS(ESI) m/z 736.1 [M+H]⁺.

Synthesis of methyl((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(17). Methyl (S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate(9.2 g, 45 mmol) and 4-bromo-2,6-difluorobenzaldehyde (10 g, 45 mmol)were stirred in THF at room temperature for 60 minutes.4-methylbenzenesulfonic acid monohydrate (9.0 g, 48 mmol) was added andthe mixture was stirred for an addition 75 minutes. The mixture wascooled to 8° C., followed by addition of NaCNBH₃ (3.8 g, 61 mmol). Thereaction was observed to exotherm to 30° C. The mixture was stirred for4 hours at room followed by dilution with DCM (200 mL) and quenchingwith 1M K₃PO₄ to pH 12. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product wascombined with tert-butyl((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (8.5 g, 22mmol) in isopropanol (30 mL) and heptanes (40 mL). The mixture wasstirred at reflux for 40 hours, after which time it was cooled to roomtemperature and diluted with 15 mL hexanes. The product (I7a) wascollected by filtration and the solids rinsed with 20% IPA in hexanes.MS (ESI) m/z 797.8 [M+H]⁺.

The title compound I7 was prepared according to the method presented forthe synthesis of compound I1 but instead utilizing methyl(S)-(1-(2-(4-bromo-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I7a) MS (ESI) m/z 869.72 [M+H]. ¹H NMR (400 MHz, Methanol-d₄) δ 7.53(d, J=7.9 Hz, 2H), 7.16 (d, J=6.9 Hz, 2H), 7.00 (d, J=8.2 Hz, 2H),4.16-4.03 (m, 2H), 3.95-3.83 (m, 2H), 3.76-3.57 (m, 11H), 2.90-2.72 (m,6H), 0.86 (d, J=23.1 Hz, 18H).

Synthesis of methyl((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(18). Intermediates: I7, and S25. MS (ESI) m/z 1052.92 [M+H]. ¹H NMR(400 MHz, Methanol-d₄) δ 8.19 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.35 (d,J=7.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 7.17 (d, J=6.9 Hz, 2H), 6.98 (t,J=10.5 Hz, 1H), 4.69 (t, J=6.8 Hz, 2H), 4.21-4.00 (m, 4H), 3.98-3.81 (m,5H), 3.80-3.62 (m, 9H), 3.25-3.09 (m, 2H), 2.98-2.85 (m, 2H), 2.79 (d,J=6.6 Hz, 2H), 2.30-2.08 (m, 1H), 2.02-1.72 (m, 6H), 0.87 (d, J=21.7 Hz,22H).

Methyl((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I9). A solution of methyl(S)-(4,4,4-trifluoro-1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamateHCl salt (200 mg, 0.68 mmol) and4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P4)(190 mg, 0.75 mmol) in ethanol (5 mL) and acetic acid (0.5 mL) wasstirred at 50° C. for 1 hour. The reaction was then cooled to roomtemperature, diluted with EtOAc, rinsed with aq NaHCO₃, dried overNa2SO4, filtered, and concentrated in vacuo. The crude mixture wasredissolved in MeTHF (10 mL) and cooled to 5° C. SODIUM CYANOBOROHYDRIDE(64 mg, 1.0 mmol) was added followed by 4-methylbenzenesulfonic acidmonohydrate (155 mg, 0.82 mmol). After 1 hour, the reaction was warmedto room temperature and additional SODIUM CYANOBOROHYDRIDE (64 mg, 1.0mmol) and 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol)were added. After an additional 30 minutes, the reaction was quenchedwith 2M NaOH to pH 14. The mixture was then stirred at 40° C. for 30minutes. The mixture was cooled to room temperature, diluted with EtOAc,and the aqueous layer was removed. The organic layer was dried overNa2SO4, filtered, concentrated in vacuo, and purified by columnchromatography (30%→70% EtOAc in hexanes) to provide methyl(S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I9a). 1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J=2.8 Hz, 1H), 7.35 (d,J=7.9 Hz, 2H), 7.22 (t, J=60.7 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 5.34 (d,J=9.7 Hz, 1H), 4.30 (d, J=9.7 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.06 (d,J=13.0 Hz, 1H), 3.67 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H). MS (ESI) m/z499.2 [M+H].

Methyl(S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I9a) (0.25 g, 0.50 mmol) was combined with tert-butyl((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (0.21 g, 0.55mmol) in heptanes (4 mL) and IPA (2 mL). The mixture was stirred at 90°C. in a sealed tube overnight. The crude mixture was cooled to roomtemperature, concentrated in vacuo, and redissolved in DCM (10 mL), andcooled to 5° C. 4M Hydrochloric acid (4.0M in dioxane, 0.89 ml) wasadded and the mixture was stirred overnight, allowing to slowly warm toroom temperature. Concentration in vacuo provided methyl((S)-1-(2-((2S,3S)-3-amino-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(I9b) as an HCl salt. MS (ESI) m/z 787.9 [M+H]. This crude salt (I9b)was combined in DCM (5 mL) with(S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoicacid (A1) (0.11 g, 0.38 mmol) and DIPEA (0.27 ml, 2 mmol). HATU (0.14 g,0.36 mmol) was added. After 20 minutes the reaction was quenched with aqNaOH, the organic layer was separated, dried over Na2SO4, filtered, andconcentrated in vacuo, The resulting mixture was redissolved in DCM and4M HCl in dioxane (0.76 ml) was added. After 3.5 hours, the mixture wasconcentrated in vacuo to provide methyl((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamateas an HCl salt that was used without further purification. MS (ESI) m/z956.2 [M+H].

3. Example Compounds, Synthesis, and Characterization

Example 1

Synthesis of methyl((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(1a). Combined P10 (289.23 mg, 0.88 mmol) and I2 (486 mg, 0.63 mmol)were stirred in a 3:1 mixture of THF/AcOH (7.0 mL) at 55° C. for 1h. Themixture was cooled to room temperature and polymer supported sodiumcyanoborohydride (2.49 mmol/g, 780.02 mg, 1.94 mmol) was added and thereaction mixture was stirred at room temperature for 2h, and then at 28°C. overnight and 35° C. for 3h. The mixture was cooled to roomtemperature, filtered, concentrated under reduced pressure and theresidue was purified by column chromatography (45% to 75% EtOAc/Hexanes)to afford 1a MS (ESI) m/z 1028.3 [M+H]⁺.

Synthesis of methyl((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(1) In a vial, a solution of 1a (28 mg, 0.027 mmol), S6 (10.4 mg, 0.041mmol), copper (I) iodide (0.52 mg, 0.002 mmol),trans-Dichlorobis(triphenylphosphine)palladium (II) (99%, 0.87 mg, 0.004mmol) in a mixture of and MeCN:Et₃N 3:1(1 mL) was degassed and thenheated to 25° C. for 25 min. Concentrated under reduced pressure. Theresidue was purified by HPLC and Lyophilized to give 1. MS (ESI) m/z1131.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1H), 8.10 (d,J=9.3 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 7.28 (d,J=8.4 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 7.05 (d, J=9.9 Hz, 1H), 6.82 (d,J=9.0 Hz, 1H), 6.76 (d, J=9.8 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.32-5.96(m, 1H), 4.96 (s, 1H), 4.61 (dd, J=8.2, 4.7 Hz, 1H), 4.58-4.49 (m, 3H),4.45 (dd, J=14.2, 4.8 Hz, 1H), 4.37 (s, 1H), 4.21 (d, J=9.9 Hz, 1H),4.04 (d, J=13.0 Hz, 2H), 3.84 (d, J=13.2 Hz, 1H), 3.74 (d, J=11.9 Hz,1H), 3.67 (d, J=11.5 Hz, 2H), 3.54 (s, 4H), 3.47 (s, 3H), 2.92-2.73 (m,4H), 2.73-2.62 (m, 1H), 2.24 (s, 2H), 1.05 (d, J=4.5 Hz, 7H), 1.01 (s,3H), 0.92 (s, 3H).

Example 2

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(2) Intermediates: I3, P1, and S7. MS (ESI) m/z 1102.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.53 (d, J=0.8 Hz, 2H), 8.21 (d, J=9.3 Hz, 1H),8.17 (d, J=1.2 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.59 (t, J=59.9 Hz, 1H),7.37 (dd, J=19.9, 8.1 Hz, 5H), 7.23 (d, J=7.9 Hz, 3H), 6.83 (d, J=9.9Hz, 1H), 4.96 (t, J=7.6 Hz, 3H), 4.81 (dd, J=8.2, 5.0 Hz, 3H), 4.44 (d,J=9.9 Hz, 1H), 4.12 (d, J=19.4 Hz, 6H), 3.95 (d, J=13.2 Hz, 1H), 3.75(d, J=10.1 Hz, 3H), 3.69 (d, J=0.8 Hz, 4H), 3.65 (s, 4H), 3.46 (d,J=14.4 Hz, 3H), 2.90 (d, J=8.9 Hz, 2H), 2.79 (d, J=8.9 Hz, 2H),2.25-2.12 (m, 3H), 1.99 (d, J=8.8 Hz, 2H), 1.14 (s, 4H), 1.10 (s, 4H),0.86 (s, 12H).

Example 3

Methyl((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(3). Intermediates: I2, P12, and S3. MS (ESI) m/z 1133.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.29 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.5 Hz, 1H),7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.60 (d, J=1.9 Hz, 1H), 7.53 (d, J=7.9 Hz,2H), 7.36 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz,2H), 7.15 (d, J=9.7 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.78 (d, J=10.0 Hz,1H), 6.35 (d, J=1.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.81-4.76 (m, 2H),4.47 (td, J=13.6, 4.3 Hz, 2H), 4.37 (dd, J=19.3, 11.6 Hz, 2H), 4.25 (d,J=9.7 Hz, 1H), 4.15 (s, 2H), 3.99 (d, J=9.2 Hz, 2H), 3.74 (s, 1H), 3.68(s, 3H), 3.60 (s, 3H), 3.39 (s, 1H), 3.36 (s, 1H), 2.90 (d, J=9.0 Hz,2H), 2.86-2.72 (m, 1H), 2.22 (d, J=8.5 Hz, 2H), 2.07 (d, J=8.6 Hz, 1H),1.11 (s, 6H), 1.06 (s, 3H), 0.81 (s, 3H).

Example 4

methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(3-methyloxetane-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(4). Intermediates: 11, P41, and S64. MS (ESI) m/z 1053.33 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.21 (dd, J=2.2, 0.7 Hz, 1H), 7.90-7.69 (m,2H), 7.61 (d, J=2.3 Hz, 1H), 7.33 (t, J=8.4 Hz, 5H), 7.24 (d, J=8.0 Hz,2H), 6.98 (d, J=9.2 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 5.06 (s, 1H), 4.93(s, 1H), 4.41 (d, J=6.0 Hz, 2H), 4.22-4.02 (m, 4H), 3.91 (d, J=13.2 Hz,6H), 3.79-3.54 (m, 9H), 3.20 (d, J=12.0 Hz, 2H), 2.92 (h, J=5.7, 4.9 Hz,2H), 2.81 (d, J=7.9 Hz, 2H), 2.08-1.80 (m, 6H), 1.69 (s, 3H), 0.87 (d,J=20.1 Hz, 21H).

Example 5

methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(5) Intermediates: I3, P13, and S3. MS (ESI) m/z 1091.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=2.3 Hz, 1H), 8.10 (d, J=9.4 Hz, 1H),7.60 (dt, J=5.5, 2.7 Hz, 2H), 7.24 (t, J=7.8 Hz, 4H), 7.12 (d, J=8.1 Hz,2H), 6.77 (d, J=8.9 Hz, 1H), 6.71 (d, J=9.9 Hz, 1H), 6.54 (d, J=2.4 Hz,1H), 4.95-4.85 (m, 2H), 4.71 (dd, J=8.3, 5.0 Hz, 2H), 4.34 (d, J=10.0Hz, 1H), 4.26 (d, J=14.3 Hz, 2H), 4.11-3.94 (m, 4H), 3.87 (s, 1H), 3.84(s, 0H), 3.67 (s, 1H), 3.59 (s, 4H), 3.56 (s, 3H), 3.28 (d, J=13.9 Hz,2H), 2.80 (d, J=9.1 Hz, 2H), 2.69 (d, J=8.9 Hz, 2H), 2.21-2.04 (m, 2H),1.98 (d, J=8.6 Hz, 2H), 1.04 (s, 4H), 1.00 (s, 3H), 0.99-0.94 (m, 1H),0.77 (s, 9H).

Example 6

methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(6) Intermediates: I3, P10, and S3. MS (ESI) m/z 1115.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H),7.64 (d, J=2.4 Hz, 1H), 7.61 (dd, J=8.8, 2.3 Hz, 1H), 7.28 (d, J=8.4 Hz,2H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 6.77 (d, J=9.0 Hz,1H), 6.72 (d, J=9.9 Hz, 0H), 6.65 (d, J=2.4 Hz, 1H), 6.12 (tt, J=55.3,4.0 Hz, 1H), 4.87 (dd, J=8.3, 7.0 Hz, 2H), 4.71 (dd, J=8.3, 5.0 Hz, 2H),4.54-4.42 (m, 2H), 4.38-4.31 (m, 1H), 4.26 (d, J=13.8 Hz, 2H), 4.13-3.97(m, 4H), 3.85 (s, 0H), 3.67 (s, 1H), 3.59 (s, 2H), 3.55 (s, 3H), 3.30(s, 1H), 3.26 (s, 1H), 2.81 (d, J=9.3 Hz, 2H), 2.70 (d, J=9.4 Hz, 2H),2.17-2.06 (m, 2H), 1.98 (d, J=8.6 Hz, 2H), 1.05 (s, 3H), 1.01 (s, 3H),0.77 (s, 9H).

Example 7

methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(7). Intermediates: I3, P10, and S7. MS (ESI) m/z 1117.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.44 (s, 2H), 8.11 (d, J=9.4 Hz, 1H), 7.64 (d,J=2.4 Hz, 1H), 7.26 (dd, J=14.0, 8.2 Hz, 4H), 7.14 (d, J=8.1 Hz, 2H),6.73 (d, J=10.0 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.12 (tt, J=55.3, 4.0Hz, 1H), 4.95-4.82 (m, 2H), 4.74-4.62 (m, 3H), 4.51 (td, J=14.3, 4.0 Hz,2H), 4.35 (d, J=9.9 Hz, 1H), 4.02 (d, J=19.0 Hz, 4H), 3.86 (d, J=13.2Hz, 1H), 3.67 (s, 1H), 3.59 (s, 3H), 3.55 (s, 3H), 3.37 (d, J=14.5 Hz,2H), 2.81 (d, J=8.9 Hz, 2H), 2.70 (d, J=9.3 Hz, 2H), 2.23-2.02 (m, 2H),1.98-1.83 (m, 2H), 1.04 (s, 3H), 1.01 (s, 3H), 0.77 (s, 9H).

Example 8

methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(8). Intermediates: I3, P10, and S6. MS (ESI) m/z 1101.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H), 8.08 (d, J=9.4 Hz, 1H),7.64 (d, J=2.4 Hz, 1H), 7.61 (dd, J=8.8, 2.2 Hz, 1H), 7.25 (dd, J=21.0,8.1 Hz, 3H), 7.12 (d, J=8.0 Hz, 2H), 6.70 (d, J=10.3 Hz, 0H), 6.64 (d,J=2.4 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 6.12 (tt, J=55.2, 3.9 Hz, 1H),4.96 (s, 1H), 4.91-4.82 (m, 1H), 4.61 (dd, J=8.4, 4.6 Hz, 1H), 4.57-4.42(m, 3H), 4.41 (s, 1H), 4.35 (d, J=6.5 Hz, 1H), 4.02 (d, J=13.2 Hz, 2H),3.87 (d, J=13.2 Hz, 1H), 3.72-3.61 (m, 3H), 3.59 (s, 3H), 3.55 (s, 2H),2.80 (d, J=8.7 Hz, 1H), 2.70 (d, J=9.5 Hz, 2H), 2.24 (s, 2H), 1.05 (s,3H), 1.01 (s, 3H), 0.77 (s, 8H).

Example 9

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(9). Intermediates: I2, P34, and S6. MS (ESI) m/z 1101.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.16 (d, J=2.1 Hz, 1H), 8.10 (d, J=9.4 Hz, 1H),7.60 (d, J=8.3 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H),7.13 (d, J=8.0 Hz, 2H), 6.76 (d, J=10.1 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H),4.96 (s, 1H), 4.61 (s, 1H), 4.49 (t, J=8.9 Hz, 1H), 4.41 (s, 1H), 4.35(d, J=9.7 Hz, 1H), 4.18 (d, J=9.9 Hz, 1H), 4.09 (d, J=13.1 Hz, 1H), 3.87(d, J=13.1 Hz, 1H), 3.77-3.55 (m, 8H), 2.82 (d, J=8.5 Hz, 3H), 2.71 (d,J=10.1 Hz, 1H), 2.54 (s, 3H), 2.23 (s, 2H), 1.05 (d, J=7.7 Hz, 9H), 0.92(s, 3H).

Example 10

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(10). Intermediates: I2, P10, and S8. MS (ESI) m/z 1143.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.26-8.19 (m, 1H), 8.10 (d, J=9.4 Hz, 1H), 7.65(d, J=2.5 Hz, 1H), 7.61 (dd, J=8.9, 2.3 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H),7.24 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.9 Hz, 1H),6.72 (d, J=10.0 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.30-5.97 (m, 1H), 4.51(td, J=14.2, 3.9 Hz, 3H), 4.35 (d, J=9.7 Hz, 1H), 4.22 (d, J=10.0 Hz,1H), 4.04 (d, J=12.4 Hz, 4H), 3.60 (s, 3H), 3.57 (s, 3H), 3.48 (d,J=11.0 Hz, 1H), 2.89-2.61 (m, 5H), 1.08 (s, 4H), 1.05 (s, 3H), 1.02 (s,3H), 0.94 (s, 3H).

Example 11

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(11). Intermediates: I2, P34, and S3. MS (ESI) m/z 1121.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=2.3 Hz, 1H), 8.08 (d, J=9.4 Hz, 1H),7.60 (dd, J=8.9, 2.3 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.24 (d, J=7.9 Hz,2H), 7.13 (d, J=8.1 Hz, 2H), 7.08 (d, J=10.5 Hz, 1H), 6.77 (d, J=9.0 Hz,1H), 6.73 (d, J=9.9 Hz, 1H), 4.93-4.82 (m, 2H), 4.74-4.63 (m, 2H), 4.34(d, J=9.9 Hz, 1H), 4.26 (d, J=13.5 Hz, 1H), 4.18 (d, J=10.0 Hz, 1H),4.09 (d, J=17.9 Hz, 4H), 3.88 (d, J=13.1 Hz, 1H), 3.64 (s, 1H), 3.60 (d,J=2.9 Hz, 6H), 3.28 (d, J=13.8 Hz, 2H), 2.82 (d, J=8.6 Hz, 3H),2.75-2.62 (m, 1H), 2.54 (s, 3H), 2.22-2.06 (m, 2H), 1.98 (d, J=8.6 Hz,2H), 1.06 (s, 6H), 1.04 (s, 3H), 0.93 (s, 3H).

Example 12

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(12). Intermediates: I3, P4, and S4. MS (ESI) m/z 1087.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 8.10 (d,J=2.8 Hz, 1H), 7.78-7.71 (m, 1H), 7.52 (t, J=59.9 Hz, 1H), 7.45 (d,J=8.2 Hz, 2H), 7.33 (d, J=7.8 Hz, 3H), 7.22 (d, J=7.9 Hz, 3H), 6.93 (d,J=2.7 Hz, 1H), 6.78 (d, J=9.2 Hz, 2H), 4.70-4.57 (m, 2H), 4.44 (d, J=9.7Hz, 1H), 4.13 (d, J=12.4 Hz, 3H), 3.97 (d, J=13.0 Hz, 1H), 3.76 (s, 1H),3.69 (s, 4H), 3.65 (s, 3H), 2.90 (d, J=8.7 Hz, 2H), 2.80 (d, J=11.1 Hz,2H), 2.11 (d, J=10.6 Hz, 1H), 1.39-1.23 (m, 2H), 1.15 (s, 4H), 1.11 (s,4H), 0.86 (s, 11H).

Example 13

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(13). Intermediates: I3, P4, and S8. MS (ESI) m/z 1073.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.30 (d, J=2.2 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H),8.10 (d, J=2.7 Hz, 1H), 7.75-7.59 (m, 2H), 7.56 (dd, J=7.4, 3.4 Hz, 1H),7.53 (t, J=59.8 Hz, 2H), 7.45 (d, J=8.2 Hz, 3H), 7.32 (d, J=7.9 Hz, 3H),7.22 (d, J=8.1 Hz, 3H), 7.03-6.88 (m, 3H), 6.82 (d, J=10.0 Hz, 1H), 4.62(dd, J=22.7, 13.0 Hz, 2H), 4.44 (d, J=9.7 Hz, 1H), 4.12 (d, J=12.2 Hz,6H), 3.97 (d, J=13.1 Hz, 2H), 3.85 (t, J=12.6 Hz, 1H), 3.76 (s, 2H),3.69 (s, 4H), 3.59 (d, J=10.8 Hz, 2H), 3.01-2.70 (m, 6H), 1.14 (s, 4H),1.11 (s, 4H), 0.86 (s, 12H).

Example 14

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(14). Intermediates: I2, P17, and S3. MS (ESI) m/z 1176.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=2.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H),7.68-7.58 (m, 2H), 7.25 (dd, J=13.9, 8.3 Hz, 4H), 7.12 (d, J=8.0 Hz,2H), 6.75 (dd, J=17.1, 9.4 Hz, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.97 (dq,J=8.2, 3.8 Hz, 1H), 4.87 (t, J=7.6 Hz, 3H), 4.71 (dd, J=8.3, 5.0 Hz,3H), 4.52-4.32 (m, 1H), 4.32-4.18 (m, 3H), 4.17-3.99 (m, 6H), 3.97 (d,J=4.7 Hz, 2H), 3.84 (td, J=8.3, 5.4 Hz, 2H), 3.58 (d, J=9.5 Hz, 8H),3.27 (d, J=13.9 Hz, 3H), 2.80-2.52 (m, 4H), 2.45-2.33 (m, 1H), 2.33-2.23(m, 1H), 2.13 (d, J=10.7 Hz, 2H), 2.03-1.92 (m, 2H), 1.07 (s, 4H), 1.05(s, 3H), 1.00 (s, 3H), 0.94 (s, 3H).

Example 15

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(15). Intermediates: I2, P18, and S3. MS (ESI) m/z 1176.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J=9.4 Hz, 1H), 7.63 (d,J=2.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.25 (dd, J=14.4, 8.2 Hz, 4H),7.12 (d, J=8.0 Hz, 2H), 6.74 (t, J=10.2 Hz, 2H), 6.59 (d, J=2.4 Hz, 1H),4.98 (dd, J=8.3, 3.9 Hz, 1H), 4.69 (t, J=6.7 Hz, 2H), 4.35 (d, J=9.9 Hz,1H), 4.22 (d, J=10.0 Hz, 1H), 4.03 (dd, J=14.5, 7.1 Hz, 3H), 3.97 (d,J=4.7 Hz, 2H), 3.90-3.79 (m, 2H), 3.63 (s, 1H), 3.58 (d, J=9.2 Hz, 6H),2.81 (d, J=7.8 Hz, 2H), 2.68 (d, J=10.0 Hz, 1H), 2.49-2.33 (m, 1H),2.33-2.21 (m, 1H), 2.10 (s, 1H), 1.94 (s, 0H), 1.07 (s, 3H), 1.05 (s,3H), 1.00 (s, 3H), 0.94 (s, 3H).

Example 16

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(16). Intermediates: I2, P19, and S3. MS (ESI) m/z 1177.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.61 (s,1H), 7.59 (d, J=2.3 Hz, 2H), 7.25 (dd, J=12.2, 8.1 Hz, 4H), 7.12 (d,J=8.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 1H), 6.72 (d, J=10.2 Hz, 1H), 6.60 (d,J=2.4 Hz, 1H), 4.87 (t, J=7.6 Hz, 3H), 4.71 (dd, J=8.3, 5.0 Hz, 2H),4.35 (d, J=9.9 Hz, 1H), 4.30-4.13 (m, 2H), 4.03 (d, J=12.6 Hz, 3H), 3.84(d, J=13.3 Hz, 1H), 3.58 (d, J=8.2 Hz, 5H), 3.28 (d, J=13.9 Hz, 2H),2.81 (d, J=7.8 Hz, 2H), 2.72 (d, J=15.2 Hz, 1H), 2.12 (s, 1H), 1.98 (d,J=8.6 Hz, 2H), 1.10 (s, 6H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H),0.93 (s, 3H).

Example 17

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(8-(dimethylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(17). Intermediates: I2, P7, and S24. MS (ESI) m/z 1177.2 [M+H]^(|). 1HNMR (400 MHz, Methanol-d4) δ 8.53 (d, J=0.7 Hz, 1H), 8.22-8.13 (m, 2H),8.11 (s, 1H), 7.86 (dd, J=9.3, 2.2 Hz, 1H), 7.50 (s, 1H), 7.40-7.30 (m,2H), 7.23 (dd, J=8.2, 5.7 Hz, 4H), 7.17 (d, J=9.9 Hz, 1H), 7.10 (d,J=9.3 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 4.50-4.37 (m, 1H), 4.35-4.23 (m,3H), 4.12 (t, J=11.1 Hz, 2H), 4.00-3.87 (m, 3H), 3.66 (d, J=10.3 Hz,7H), 3.43-3.33 (m, 2H), 2.96 (s, 6H), 2.94-2.69 (m, 2H), 1.96 (t, J=5.3Hz, 2H), 1.78 (t, J=6.9 Hz, 2H), 1.26-1.07 (m, 9H), 1.02 (s, 3H).

Example 18

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(18). Intermediates: I2, P7, and S25. MS (ESI) m/z 1177.2 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.13-8.05 (m, 2H), 8.03 (s,1H), 7.68 (t, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.31-7.22 (m, 2H), 7.20-7.05(m, 5H), 6.96-6.84 (m, 1H), 6.72 (d, J=10.0 Hz, 1H), 4.75-4.65 (m, 5H),4.60 (dd, J=7.6, 6.2 Hz, 2H), 4.40-4.26 (m, 1H), 4.25-4.12 (m, 1H),4.10-3.87 (m, 4H), 3.87-3.71 (m, 3H), 3.58 (d, J=10.7 Hz, 6H), 3.17-2.96(m, 2H), 2.89-2.59 (m, 4H), 2.19-1.93 (m, 2H), 1.93-1.67 (m, 4H),1.15-0.96 (m, 9H), 0.94 (s, 3H).

Example 19

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(19). Intermediates: I2, P7, and S26. MS (ESI) m/z 1177.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.7 Hz, 1H), 8.26-8.22 (m, 1H), 8.17(d, J=9.4 Hz, 1H), 8.12 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.51 (s, 1H),7.39-7.32 (m, 2H), 7.24 (t, J=8.3 Hz, 4H), 7.17 (d, J=9.8 Hz, 1H), 7.01(d, J=9.0 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 4.80 (ddtd, J=4.5, 2.0, 1.0,0.5 Hz, 1H), 4.76-4.69 (m, 4H), 4.50-4.37 (m, 1H), 4.36-4.25 (m, 1H),4.13 (t, J=10.7 Hz, 3H), 3.93 (d, J=13.2 Hz, 1H), 3.68 (d, J=10.5 Hz,6H), 2.97-2.66 (m, 6H), 2.33-2.10 (m, 3H), 1.26-1.08 (m, 9H), 1.03 (s,3H).

Example 20

methyl((5S,8S,9S,14S)-8-(4-((6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(20). Intermediates: I2, P7, and S27. MS (ESI) m/z 1086.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.12 (s,1H), 8.08 (d, J=1.9 Hz, 1H), 7.93 (dd, J=9.4, 2.0 Hz, 1H), 7.69-7.60 (m,1H), 7.56 (dd, J=7.2, 3.3 Hz, 0H), 7.51 (s, 0H), 7.40-7.33 (m, 2H), 7.25(d, J=8.0 Hz, 4H), 7.17 (d, J=9.9 Hz, 1H), 6.83 (d, J=9.3 Hz, 1H), 4.86(s, 4H), 4.49 (s, 4H), 4.43 (d, J=3.7 Hz, 1H), 4.36-4.25 (m, 1H),4.24-4.05 (m, 2H), 3.92 (d, J=13.1 Hz, 1H), 3.67 (d, J=7.6 Hz, 7H),2.99-2.70 (m, 4H), 1.23-1.06 (m, 9H), 1.03 (s, 3H).

Example 21

methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(21). Intermediates: I2, P10, and S2. MS (ESI) m/z 1143.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.18 (d, J=2.3 Hz, 1H), 8.06 (d, J=9.3 Hz, 1H),7.64 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.9, 2.3 Hz, 1H), 7.28 (d, J=8.5 Hz,2H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.02 (d, J=9.7 Hz,1H), 6.77 (d, J=9.0 Hz, 1H), 6.71-6.61 (m, 2H), 6.12 (tt, J=55.4, 4.0Hz, 1H), 4.50 (td, J=14.3, 3.9 Hz, 2H), 4.34 (d, J=9.6 Hz, 1H),4.29-4.18 (m, 1H), 4.04 (d, J=13.0 Hz, 6H), 3.84 (d, J=13.2 Hz, 1H),3.63 (s, 3H), 3.56 (s, 3H), 3.50 (s, 2H), 3.10 (s, 3H), 2.81 (d, J=8.1Hz, 2H), 2.69 (d, J=9.4 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s,3H), 0.94 (s, 3H).

Example 22

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(22). Intermediates 11, P41, and S3. MS (ESI) m/z 1011.29 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄)) δ 8.30 (d, J=2.2 Hz, 1H), 7.70 (dd, J=8.8, 2.3Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.33 (d, J=7.7 Hz, 5H), 7.23 (d, J=7.8Hz, 2H), 6.86 (d, J=8.9 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 4.96 (t, J=7.6Hz, 2H), 4.82-4.77 (m, 2H), 4.35 (d, J=13.8 Hz, 2H), 4.13 (d, J=13.4 Hz,4H), 3.93 (s, 6H), 3.67 (d, J=6.4 Hz, 8H), 3.38 (d, J=13.9 Hz, 2H),3.00-2.77 (m, 5H), 2.31-2.20 (m, 2H), 2.14-2.04 (m, 2H), 0.87 (d, J=20.7Hz, 21H).

Example 23

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(23). Intermediates: I3, P4, and S7. MS (ESI) m/z 1102.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 2H), 8.20 (d, J=9.4 Hz, 1H), 8.11 (d,J=2.7 Hz, 1H), 7.53 (t, J=59.9, 59.4 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H),7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 6.94 (d, J=2.8 Hz, 1H),6.83 (d, J=9.9 Hz, 1H), 5.03-4.92 (m, 2H), 4.83-4.76 (m, 2H), 4.44 (d,J=10.0 Hz, 1H), 4.16-4.05 (m, 2H), 3.97 (d, J=13.2 Hz, 1H), 3.85-3.71(m, 1H), 3.69 (s, 3H), 3.65 (s, 3H), 3.54-3.39 (m, 2H), 2.96-2.72 (m,3H), 2.27-2.13 (m, 2H), 2.04-1.91 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H),0.86 (s, 9H).

Example 24

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(24). Intermediates: I2, P16, and S29. MS (ESI) m/z 1104.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.87 (d, J=4.9 Hz, 2H), 8.52 (s, 2H), 8.19(d, J=9.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.41 (t, J=4.9 Hz, 1H), 7.35(d, J=8.0 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.12 (d, J=10.1 Hz, 1H), 6.82(d, J=10.1 Hz, 1H), 5.18 (s, 1H), 4.99-4.90 (m, 2H), 4.64-4.55 (m, 1H),4.44 (d, J=10.0 Hz, 1H), 4.30 (d, J=10.0 Hz, 1H), 4.24-4.10 (m, 2H),3.98 (d, J=13.0 Hz, 1H), 3.90 (d, J=12.5 Hz, 1H), 3.85-3.72 (m, 3H),3.69 (s, 3H), 3.67 (s, 3H), 2.96-2.74 (m, 4H), 2.33 (s, 2H), 1.15 (s,6H), 1.11 (s, 3H), 1.02 (s, 3H).

Example 25

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(25). Intermediates: I2, P10, and S29. MS (ESI) m/z 1156.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 2H), 8.18 (d, J=9.3 Hz, 1H), 7.37(d, J=8.5 Hz, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.14(d, J=8.8 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.22(tt, J=55.5, 4.0 Hz, 1H), 5.18 (s, 1H), 5.01-4.90 (m, 2H), 4.72 (s, 1H),4.60 (td, J=14.1, 3.7 Hz, 4H), 4.52 (s, 0H), 4.44 (d, J=9.9 Hz, 1H),4.31 (d, J=10.0 Hz, 1H), 4.20-4.07 (m, 2H), 3.98-3.86 (m, 2H), 3.81 (d,J=12.8 Hz, 1H), 3.76-3.71 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.00-2.71(m, 4H), 2.34 (s, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03(s, 3H).

Example 26

Methyl((5S,8S,9S,14S)-8-(4-((6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(26). Intermediates: I2, P4, and S28. MS (ESI) m/z 1115.4 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.17 (d, J=2.3 Hz, 1H), 8.07 (d, J=9.4 Hz,1H), 8.01 (d, J=2.8 Hz, 1H), 7.56 (dd, J=8.8, 2.4 Hz, 1H), 7.44 (t,J=59.9 Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 7.12 (d,J=8.1 Hz, 2H), 6.84 (d, J=2.7 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 6.69 (d,J=10.0 Hz, 1H), 4.70-4.61 (m, 2H), 4.34 (d, J=9.8 Hz, 1H), 4.21 (d,J=10.0 Hz, 1H), 4.08-4.00 (m, 4H), 3.94 (d, J=13.0 Hz, 2H), 3.85 (d,J=13.1 Hz, 1H), 3.64 (s, 1H), 3.60 (s, 3H), 3.58-3.54 (m, 4H), 3.42 (d,J=14.4 Hz, 3H), 2.85-2.62 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s,3H), 0.94 (s, 3H).

Example 27

Methyl((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(27). Intermediates: I2, P3, and S6. MS (ESI) m/z 1149.3 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H), 8.06 (d, J=9.4 Hz,1H), 7.60 (dd, J=8.8, 2.3 Hz, 1H), 7.42 (d, J=7.5 Hz, 2H), 7.23 (d,J=7.9 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 7.06 (d, J=10.1 Hz, 1H), 6.71 (d,J=10.0 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.96 (s, 1H), 4.92-4.78 (m, 2H),4.61 (s, 1H), 4.55-4.44 (m, 1H), 4.41 (s, 1H), 4.34 (d, J=9.8 Hz, 1H),4.19 (d, J=10.0 Hz, 1H), 4.12-4.01 (m, 2H), 3.87 (d, J=13.1 Hz, 1H),3.72-3.61 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 2.89-2.75 (m, 3H),2.73-2.61 (m, 1H), 2.43 (ddd, J=13.1, 8.5, 4.9 Hz, 1H), 2.23 (s, 2H),1.27-1.18 (m, 2H), 1.10-1.01 (m, 11H), 0.93 (s, 3H).

Example 28

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(28). Intermediates: I2, P21, and S6. MS (ESI) m/z 1095.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H), 8.02 (d, J=9.5 Hz, 1H),7.62-7.57 (m, 3H), 7.56 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.23(d, J=7.9 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.04 (s, 1H), 6.67 (d, J=9.7Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 4.96 (s, 1H),4.89-4.83 (m, 1H), 4.84-4.78 (m, 1H), 4.65-4.54 (m, 1H), 4.54-4.44 (m,2H), 4.41 (s, 1H), 4.30 (d, J=9.9 Hz, 1H), 4.16 (d, J=9.7 Hz, 1H),4.12-4.00 (m, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.78 (d, J=13.5 Hz, 1H),3.73-3.60 (m, 2H), 3.60-3.53 (m, 4H), 3.51 (s, 3H), 2.87-2.76 (m, 2H),2.76-2.59 (m, 2H), 2.23 (s, 2H), 1.07-0.94 (m, 10H), 0.92 (s, 3H), 0.72(s, 3H).

Example 29

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(29). Intermediates: I2, P6, and S6. MS (ESI) m/z 1105.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.25 (d, J=2.2 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H),8.05 (d, J=2.7 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (dd, J=8.8, 2.3 Hz,1H), 7.49 (t, J=59.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.32 (d, J=7.9 Hz,2H), 7.22 (d, J=8.1 Hz, 2H), 7.12 (d, J=9.4 Hz, 1H), 6.86 (d, J=2.7 Hz,1H), 6.77 (d, J=9.9 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.05 (s, 1H), 4.95(dd, J=8.4, 6.5 Hz, 1H), 4.93-4.87 (m, 1H), 4.70 (dd, J=8.5, 4.6 Hz,1H), 4.66-4.53 (m, 2H), 4.50 (s, 1H), 4.40 (d, J=9.9 Hz, 1H), 4.24 (d,J=9.8 Hz, 1H), 4.21-4.12 (m, 1H), 4.01 (d, J=13.2 Hz, 1H), 3.88 (d,J=13.2 Hz, 1H), 3.82-3.69 (m, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 2.96-2.66(m, 4H), 2.33 (s, 2H), 1.12 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 0.83(s, 3H).

Example 30

methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(30). Intermediates: I2, P21, and S29. MS (ESI) m/z 1096.7 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 2H), 8.10 (d, J=9.0 Hz, 1H), 7.68(d, J=8.0 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.40 (d, J=7.9 Hz, 2H), 7.34(d, J=7.8 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 6.76 (d, J=10.1 Hz, 1H), 6.56(d, J=2.4 Hz, 1H), 5.18 (s, 1H), 4.93 (dt, J=20.6, 7.3 Hz, 1H), 4.72 (s,1H), 4.65-4.55 (m, 1H), 4.51 (s, 0H), 4.40 (d, J=7.8 Hz, 1H), 4.25 (d,J=7.8 Hz, 1H), 4.15 (s, 1H), 4.02-3.78 (m, 3H), 3.67 (s, 3H), 3.66 (d,J=3.8 Hz, 1H), 3.59 (s, 3H), 2.94-2.67 (m, 4H), 2.41-2.30 (m, 2H),2.05-1.99 (m, 1H), 1.93 (s, 1H), 1.15-1.04 (m, 10H), 1.01 (s, 3H), 0.81(s, 3H).

Example 31

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(31). Intermediates: I2, P13, and S29. MS (ESI) m/z 1132.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 2H), 8.15 (d, J=9.4 Hz, 1H), 7.69(d, J=2.4 Hz, 1H), 7.38-7.27 (m, 4H), 7.23 (d, J=8.0 Hz, 2H), 7.10 (d,J=10.0 Hz, 1H), 6.77 (d, J=9.8 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 5.18 (s,1H), 4.93 (dt, J=20.5, 7.3 Hz, 2H), 4.72 (s, 1H), 4.60 (td, J=12.1,11.2, 5.5 Hz, 1H), 4.51 (s, 1H), 4.46-4.39 (m, 1H), 4.36-4.24 (m, 1H),4.18-4.07 (m, 2H), 3.93 (d, J=11.4 Hz, 1H), 3.89 (s, 1H), 3.80 (d,J=12.7 Hz, 1H), 3.76-3.67 (m, 5H), 3.66 (s, 2H), 2.96-2.70 (m, 4H), 2.33(s, 2H), 1.22-1.04 (m, 12H), 1.02 (s, 3H).

Example 32

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(32). Intermediates: I2, P4, and S29. MS (ESI) m/z 1142.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.51 (s, 2H), 8.14 (d, J=9.3 Hz, 1H), 8.10 (d,J=2.7 Hz, 1H), 7.52 (t, J=59.9 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.34 (d,J=7.9 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.09 (d, J=9.6 Hz, 1H), 6.93 (d,J=2.7 Hz, 1H), 6.78 (d, J=9.9 Hz, 1H), 5.18 (s, 1H), 4.93 (dt, J=20.5,7.3 Hz, 2H), 4.71 (s, 1H), 4.60 (dq, J=11.6, 6.2, 5.6 Hz, 2H), 4.51 (s,1H), 4.44 (d, J=9.8 Hz, 1H), 4.30 (d, J=9.9 Hz, 1H), 4.21-4.05 (m, 2H),3.94 (d, J=13.5 Hz, 1H), 3.90 (d, J=12.9 Hz, 1H), 3.80 (d, J=12.6 Hz,1H), 3.77-3.70 (m, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 2.96-2.72 (m, 4H),2.44-2.24 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s,3H).

Example 33

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(33). Intermediates: I2, P21, and S7. MS (ESI) m/z 1142.4 [M+H]⁺. 1H NMR(400 MHz, Methanol-d4) δ 8.52 (s, 2H), 8.10 (d, J=9.5 Hz, 1H), 7.68 (d,J=8.1 Hz, 2H), 7.64 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.34 (d,J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.5 Hz, 1H), 6.75 (d,J=9.7 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.82-4.71(m, 3H), 4.39 (d, J=9.9 Hz, 1H), 4.24 (d, J=9.7 Hz, 1H), 4.20-4.06 (m,2H), 3.97 (d, J=13.2 Hz, 1H), 3.87 (d, J=13.4 Hz, 1H), 3.77-3.71 (m,1H), 3.67 (s, 4H), 3.59 (s, 3H), 3.45 (d, J=14.6 Hz, 2H), 2.93-2.86 (m,2H), 2.85-2.67 (m, 1H), 2.31-2.15 (m, 2H), 2.06-1.93 (m, 2H), 1.15-1.03(m, 10H), 1.01 (s, 3H), 0.82 (s, 3H).

Example 34

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(34). Intermediates: I2, P21, and S3. MS (ESI) m/z 1109.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=2.3 Hz, 1H), 8.03 (d, J=9.5 Hz, 1H),7.66-7.58 (m, 3H), 7.56 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.23(d, J=7.9 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.07 (d, J=9.5 Hz, 1H), 6.76(d, J=8.9 Hz, 1H), 6.68 (d, J=10.0 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H),4.92-4.82 (m, 2H), 4.74-4.66 (m, 2H), 4.34-4.21 (m, 3H), 4.18-4.12 (m,1H), 4.11-3.99 (m, 3H), 3.88 (d, J=13.1 Hz, 1H), 3.78 (d, J=13.3 Hz,1H), 3.65 (d, J=9.0 Hz, 1H), 3.60-3.53 (m, 4H), 3.51 (s, 3H), 3.28 (d,J=13.8 Hz, 2H), 2.86-2.76 (m, 2H), 2.76-2.56 (m, 2H), 2.17-2.08 (m, 2H),2.03-1.92 (m, 2H), 1.07-0.89 (m, 13H), 0.72 (s, 3H).

Example 35

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(35). Intermediates: I2, P13, and S2. MS (ESI) m/z 1119.5 [M+H]⁺. 1H NMR(400 MHz, Methanol-d4) δ 8.27 (dd, J=2.3, 0.7 Hz, 1H), 8.16 (d, J=9.4Hz, 1H), 7.73 (dd, J=9.0, 2.3 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.41-7.26(m, 4H), 7.21 (d, J=8.2 Hz, 2H), 7.13 (d, J=9.8 Hz, 1H), 6.96 (d, J=9.0Hz, 1H), 6.79 (d, J=9.9 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.64 (d, J=14.7Hz, 2H), 4.53-4.41 (m, 1H), 4.35-4.25 (m, 1H), 4.22-4.06 (m, 7H), 3.93(d, J=13.2 Hz, 1H), 3.78 (dt, J=14.9, 3.0 Hz, 2H), 3.73-3.67 (m, 4H),3.66 (s, 3H), 3.63 (s, 2H), 3.19 (s, 3H), 2.94-2.72 (m, 4H), 1.21-0.99(m, 16H).

Example 36

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(36). Intermediates: I2, P10, and S7. MS (ESI) m/z 1170.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 2H), 8.19 (d, J=9.3 Hz, 1H), 7.74 (d,J=2.4 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.23 (d,J=8.1 Hz, 2H), 7.15 (d, J=10.0 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 6.74 (d,J=2.4 Hz, 1H), 6.22 (tt, J=55.3, 4.0 Hz, 1H), 5.02-4.93 (m, 2H),4.83-4.78 (m, 2H), 4.77 (s, 1H), 4.60 (td, J=14.3, 3.9 Hz, 2H), 4.44 (d,J=10.0 Hz, 1H), 4.31 (d, J=10.0 Hz, 1H), 4.22-4.03 (m, 4H), 3.93 (d,J=13.2 Hz, 1H), 3.72 (s, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.51-3.40 (m,2H), 2.96-2.81 (m, 3H), 2.81-2.72 (m, 1H), 2.27-2.12 (m, 2H), 2.04-1.94(m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 37

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(37). Intermediates: I2, P13, and S7. MS (ESI) m/z 1146.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.43 (s, 2H), 8.10 (d, J=9.3 Hz, 1H), 7.60 (d,J=2.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 4H), 7.14 (d, J=8.1 Hz, 2H), 7.07 (d,J=10.1 Hz, 1H), 6.72 (d, J=10.0 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H),4.93-4.82 (m, 2H), 4.75-4.57 (m, 4H), 4.45-4.28 (m, 1H), 4.22 (d, J=10.0Hz, 1H), 4.14-3.97 (m, 4H), 3.83 (d, J=13.2 Hz, 1H), 3.71-3.61 (m, 1H),3.59 (s, 3H), 3.57 (s, 3H), 3.42-3.32 (m, 2H), 2.86-2.63 (m, 4H),2.17-2.05 (m, 2H), 1.94-1.82 (m, 2H), 1.12-1.06 (m, 3H), 1.06-0.95 (m,10H), 0.93 (s, 3H).

Example 38

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(38). Intermediates: I2, P22, and S4. MS (ESI) m/z 1254.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.31 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H),7.80 (d, J=9.0 Hz, 1H), 7.62-7.51 (m, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.12(d, J=8.0 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 6.69 (d, J=9.0 Hz, 1H), 6.60(d, J=8.9 Hz, 1H), 4.66 (t, J=6.5 Hz, 4H), 4.40-4.31 (m, 6H), 4.04 (d,J=12.6 Hz, 2H), 3.89-3.80 (m, 3H), 3.77 (t, J=6.3 Hz, 4H), 3.61 (d,J=1.2 Hz, 3H), 3.57 (s, 3H), 3.48 (d, J=13.4 Hz, 8H), 2.89-2.55 (m, 6H),1.57 (t, J=8.8 Hz, 2H), 1.24-1.13 (m, 3H), 1.08 (s, 3H), 1.06 (s, 3H),1.03 (s, 3H), 0.95 (s, 3H).

Example 39

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(39). Intermediates: I2, P13, and S30. MS (ESI) m/z 1131.5 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.2 Hz,1H), 7.61 (d, J=2.4 Hz, 2H), 7.59 (d, J=2.2 Hz, 1H), 7.29-7.19 (m, 5H),7.12 (d, J=8.0 Hz, 2H), 6.73 (d, J=10.0 Hz, 1H), 6.63-6.52 (m, 2H), 4.95(s, 1H), 4.89-4.83 (m, 1H), 4.65-4.56 (m, 1H), 4.54-4.43 (m, 2H), 4.41(s, 1H), 4.35 (d, J=9.9 Hz, 1H), 4.22 (d, J=9.9 Hz, 1H), 4.12-3.97 (m,2H), 3.83 (d, J=13.2 Hz, 1H), 3.70 (d, J=11.8 Hz, 1H), 3.65-3.61 (m,1H), 3.59 (s, 3H), 3.57 (s, 3H), 2.86-2.60 (m, 4H), 2.23 (s, 2H),1.10-0.95 (m, 13H), 0.93 (s, 3H).

Example 40

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(40). Intermediates: I2, P13, and S4. MS (ESI) m/z 1131.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.23 (d, J=2.3 Hz, 1H), 8.09 (d, J=9.5 Hz, 1H),7.64 (dd, J=8.8, 2.3 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.4,3.3 Hz, 4H), 7.12 (d, J=8.1 Hz, 2H), 6.68 (d, J=8.9 Hz, 1H), 6.54 (d,J=2.4 Hz, 1H), 4.93-4.83 (m, 2H), 4.51 (dd, J=8.2, 4.0 Hz, 2H), 4.34 (s,1H), 4.27-4.18 (m, 1H), 4.12-3.94 (m, 4H), 3.83 (d, J=13.2 Hz, 1H),3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 2.85-2.62 (m, 4H), 2.01(d, J=11.0 Hz, 1H), 1.18 (d, J=13.9 Hz, 1H), 1.10-0.94 (m, 13H), 0.92(s, 3H).

Example 41

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(41). Intermediates: I2, P10, and S4. MS (ESI) m/z 1155.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.24 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H),7.69-7.60 (m, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 7.13(d, J=8.1 Hz, 2H), 6.69 (d, J=9.0 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.13(tt, J=55.3, 3.9 Hz, 1H), 4.58-4.42 (m, 4H), 4.35 (s, 1H), 4.27-4.18 (m,1H), 4.16-3.95 (m, 4H), 3.84 (d, J=13.3 Hz, 1H), 3.63 (s, 2H), 3.60 (s,3H), 3.57 (s, 3H), 2.86-2.72 (m, 3H), 2.72-2.58 (m, 1H), 2.02 (d, J=11.0Hz, 1H), 1.19 (d, J=13.9 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s,3H), 0.93 (s, 3H).

Example 42

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(42). Intermediates: I2, P4, and S52. MS (ESI) m/z 1143.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.57 (s, 2H), 8.19 (d, J=9.4 Hz, 0H), 8.11 (d,J=2.8 Hz, 1H), 7.70-7.51 (m, 4H), 7.44 (d, J=8.2 Hz, 2H), 7.36 (d, J=7.9Hz, 2H), 7.28-7.20 (m, 2H), 6.93 (d, J=2.8 Hz, 1H), 4.65 (d, J=7.4 Hz,2H), 4.49-4.41 (m, 2H), 4.37-4.28 (m, 2H), 4.27-4.11 (m, 4H), 3.91 (dd,J=25.4, 13.9 Hz, 2H), 3.73 (s, 2H), 3.70 (s, 3H), 3.67 (s, 3H),2.94-2.83 (m, 3H), 2.83-2.70 (m, 1H), 2.09 (t, J=11.9 Hz, 1H), 1.18-1.13(m, 6H), 1.12 (s, 3H), 1.02 (s, 3H).

Example 43

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(43). Intermediates: I2, P10, and S6. MS (ESI) m/z 1155.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.25 (d, J=1.9 Hz, 1H), 8.19 (d, J=9.4 Hz, 1H),7.74 (d, J=2.5 Hz, 1H), 7.69 (dd, J=8.6, 2.3 Hz, 1H), 7.38 (d, J=8.4 Hz,2H), 7.32 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.82 (d, J=9.9 Hz,1H), 6.75 (d, J=2.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.39-6.05 (m, 1H),5.06-5.02 (m, 1H), 4.74-4.67 (m, 1H), 4.65-4.53 (m, 2H), 4.50 (s, 1H),4.44 (d, J=9.9 Hz, 1H), 4.31 (d, J=10.0 Hz, 1H), 4.13 (d, J=13.4 Hz,2H), 3.93 (d, J=13.3 Hz, 1H), 3.83-3.72 (m, 2H), 3.69 (s, 3H), 3.66 (s,3H), 2.94-2.72 (m, 2H), 2.33 (s, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11(s, 3H), 1.02 (s, 3H).

Example 44

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(44). Intermediates: I2, P4, and S2. MS (ESI) m/z 1130.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.18 (d, J=2.3 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H),8.01 (d, J=2.7 Hz, 1H), 7.58 (dd, J=9.2, 2.6 Hz, 1H), 7.44 (t, J=59.7Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.12 (d, J=8.0Hz, 2H), 7.09-7.00 (m, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.9 Hz,1H), 6.72 (d, J=10.0 Hz, 1H), 4.35 (d, J=9.9 Hz, 1H), 4.21 (d, J=9.9 Hz,1H), 4.13-3.94 (m, 5H), 3.85 (d, J=13.2 Hz, 1H), 3.71-3.63 (m, 3H), 3.60(s, 3H), 3.57 (s, 3H), 3.51 (s, 2H), 3.10 (s, 3H), 2.88-2.73 (m, 3H),2.73-2.64 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s,3H).

Example 45

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(45). Intermediates: I2, P13, and S6. MS (ESI) m/z 1130.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H),7.65-7.55 (m, 2H), 7.30-7.19 (m, 4H), 7.12 (d, J=8.0 Hz, 2H), 7.08 (d,J=10.0 Hz, 1H), 6.72 (d, J=9.9 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 6.55 (d,J=2.4 Hz, 1H), 4.96 (s, 1H), 4.86 (dd, J=8.3, 6.4 Hz, 1H), 4.61 (dd,J=8.5, 4.6 Hz, 1H), 4.56-4.44 (m, 2H), 4.42 (s, 1H), 4.35 (d, J=9.8 Hz,1H), 4.22 (d, J=10.0 Hz, 1H), 4.08-3.98 (m, 2H), 3.83 (d, J=13.2 Hz,1H), 3.73-3.61 (m, 4H), 3.59 (s, 3H), 3.57 (s, 3H), 2.85-2.72 (m, 2H),2.72-2.62 (m, 1H), 2.24 (s, 2H), 1.07 (s, 3H), 1.06-0.94 (m, 10H), 0.93(s, 3H).

Example 46

Methyl((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(46). Intermediates: I2, P10, and S3. MS (ESI) m/z 1169.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.30 (d, J=2.3 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H),7.74 (d, J=2.4 Hz, 1H), 7.70 (dd, J=8.9, 2.3 Hz, 1H), 7.38 (d, J=8.4 Hz,2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.19-7.12 (m, 1H),6.86 (d, J=8.9 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H),6.22 (tt, J=55.5, 4.2 Hz, 1H), 4.97 (t, J=7.6 Hz, 3H), 4.80 (dd, J=8.2,5.0 Hz, 2H), 4.60 (td, J=14.2, 3.9 Hz, 2H), 4.44 (d, J=9.9 Hz, 1H), 4.36(d, J=13.6 Hz, 2H), 4.31 (d, J=10.0 Hz, 1H), 4.19-4.10 (m, 4H), 3.93 (d,J=13.2 Hz, 1H), 3.77-3.71 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.37 (d,J=13.8 Hz, 2H), 2.96-2.69 (m, 4H), 2.29-2.16 (m, 2H), 2.16-2.03 (m, 2H),1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 47

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridin-2-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(47). Intermediates: I2, P4, and S31. MS (ESI) m/z 1206.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.23 (d, J=9.4 Hz, 1H), 8.16-8.10 (m, 2H), 8.09(d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.54 (t, J=59.5 Hz, 1H), 7.52(d, J=9.6 Hz, 1H), 7.50-7.43 (m, 4H), 7.30 (d, J=8.0 Hz, 2H), 7.22-7.13(m, 1H), 6.95 (d, J=2.8 Hz, 1H), 6.85 (d, J=10.0 Hz, 1H), 4.99 (t, J=7.6Hz, 2H), 4.84 (dd, J=8.3, 5.0 Hz, 2H), 4.65 (d, J=14.1 Hz, 2H), 4.45 (d,J=9.9 Hz, 1H), 4.31 (d, J=9.9 Hz, 1H), 4.27-4.11 (m, 4H), 3.95 (d,J=13.2 Hz, 1H), 3.84-3.74 (m, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 2.99-2.83(m, 3H), 2.83-2.74 (m, 1H), 2.30-2.19 (m, 2H), 2.17-2.06 (m, 2H), 1.17(s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H).

Example 48

3-(5-((4-(2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-8-methyl-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-ium(48). Intermediates: I2, P4, and S54 and S55. MS (ESI) m/z 1169.4[M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J=2.5 Hz, 1H), 8.10(d, J=9.4 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.64-7.57 (m, 1H), 7.44 (t,J=60.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 7.13 (d,J=8.0 Hz, 2H), 7.07 (d, J=9.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.73 (d,J=10.6 Hz, 1H), 6.70 (d, J=9.0 Hz, 1H), 5.55-5.45 (m, 1H), 5.00-4.83 (m,4H), 4.35 (d, J=9.9 Hz, 1H), 4.21 (d, J=10.0 Hz, 1H), 4.14 (s, 2H),4.12-3.94 (m, 4H), 3.85 (d, J=13.2 Hz, 1H), 3.71-3.62 (m, 2H), 3.59 (d,J=1.2 Hz, 3H), 3.57 (d, J=1.5 Hz, 3H), 3.50 (d, J=2.0 Hz, 1H), 3.46 (s,3H), 2.88-2.73 (m, 3H), 2.73-2.63 (m, 1H), 2.49-2.38 (m, 1.5H), 2.28 (d,J=11.3 Hz, 0.5H), 2.20-2.05 (m, 2H), 1.06 (s, 3H), 1.05 (s, 3H), 1.02(s, 3H), 0.93 (s, 3H).

Example 49

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-((1R,5S)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(49). Intermediates: I2, P4, and S32. MS (ESI) m/z 1323.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (d, J=9.4 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H),7.53 (t, J=59.6 Hz, 1H), 7.50-7.40 (m, 4H), 7.20-7.11 (m, 1H), 6.94 (d,J=2.8 Hz, 1H), 6.75 (d, J=9.7 Hz, 1H), 5.00-4.91 (m, 4H), 4.83-4.68 (m,4H), 4.54-4.39 (m, 3H), 4.33-4.27 (m, 1H), 4.21-4.04 (m, 6H), 3.94 (d,J=13.1 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.51-3.39 (m, 5H), 3.00-2.72(m, 4H), 2.37-2.11 (m, 4H), 2.03-1.84 (m, 4H), 1.16 (s, 3H), 1.13 (s,3H), 1.10 (s, 3H), 1.03 (s, 3H).

Example 50

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((5-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(50). Intermediates: I2, P4, and S33. MS (ESI) m/z 1156.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.34 (d, J=1.3 Hz, 1H), 8.25 (s, 1H), 8.16 (d,J=9.3 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.53 (t, J=59.4 Hz, 1H), 7.45 (d,J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 6.93 (d,J=2.8 Hz, 1H), 4.97 (t, J=7.6 Hz, 2H), 4.82-4.76 (m, 2H), 4.47-4.36 (m,3H), 4.30 (d, J=9.9 Hz, 1H), 4.23-4.10 (m, 4H), 3.95 (d, J=12.9 Hz, 1H),3.78-3.72 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.46 (d, J=14.0 Hz, 3H),2.96-2.71 (m, 4H), 2.27-2.20 (m, 1H), 2.14-2.02 (m, 2H), 1.16 (s, 3H),1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 51

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(51). Intermediates: I2, P4, and S8. MS (ESI) m/z 1129.4 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.24-8.15 (m, 1H), 8.08 (d, J=9.4 Hz, 1H),8.01 (d, J=2.7 Hz, 1H), 7.61 (dd, J=8.8, 2.3 Hz, 1H), 7.44 (t, J=59.7Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.1Hz, 2H), 6.89-6.79 (m, 2H), 4.60-4.44 (m, 1H), 4.34 (s, 1H), 4.25-4.18(m, 1H), 4.11-3.98 (m, 4H), 3.85 (d, J=13.2 Hz, 1H), 3.76 (t, J=12.6 Hz,1H), 3.68-3.62 (m, 1H), 3.60 (s, 3H), 3.57 (s, 3H), 3.54-3.35 (m, 2H),2.85-2.74 (m, 4H), 2.73-2.64 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02(s, 3H), 0.93 (s, 3H).

Example 52

(9aR)-8-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)octahydro-5H-pyrazino[2,1-c][1,4]oxazine 5-oxide(52). To a solution of 51 (17 mg, 0.02 mmol) in CH₃CN (1 mL) was added3-Chloroperoxybenzoic acid (77%, 3.9 mg, 0.02 mmol) the mixture wasstirred for 5 min then purified by HPLC to afford 52. MS (ESI) m/z1146.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.38-8.23 (m, 1H),8.17-8.06 (m, 2H), 7.99-7.88 (m, 0H), 7.73-7.65 (m, 1H), 7.59-7.40 (m,3H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.10 (d, J=10.2 Hz,1H), 6.98-6.91 (m, 2H), 6.77 (d, J=10.1 Hz, 1H), 4.59 (d, J=14.5 Hz,1H), 4.41 (dd, J=21.3, 12.0 Hz, 2H), 4.28 (dd, J=17.0, 11.1 Hz, 2H),4.14 (d, J=12.9 Hz, 2H), 4.10-3.87 (m, 6H), 3.67 (d, J=10.5 Hz, 8H),3.26-3.12 (m, 1H), 3.00-2.73 (m, 4H), 2.02 (s, 2H), 1.24-1.10 (m, 10H),1.02 (s, 3H).

Example 53

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(53). Intermediates: I3, P28, and S3. MS (ESI) m/z 1062.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.64 (d, J=4.9 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H),8.15 (d, J=9.3 Hz, 1H), 7.91 (s, 2H), 7.70 (dd, J=8.7, 2.3 Hz, 1H), 7.60(d, J=8.5 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.86(d, J=8.9 Hz, 1H), 6.77 (d, J=10.5 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H),4.82-4.76 (m, 4H), 4.40 (dd, J=33.8, 12.0 Hz, 3H), 4.16 (d, J=12.1 Hz,4H), 4.00 (d, J=13.3 Hz, 1H), 3.79-3.60 (m, 9H), 3.37 (d, J=14.0 Hz,3H), 2.95-2.77 (m, 4H), 2.22 (s, 2H), 2.08 (d, J=8.7 Hz, 2H), 1.13 (d,J=11.3 Hz, 6H), 0.86 (s, 10H).

Example 54

4-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-1-(oxetan-3-yl)piperazine 1-oxide (54). The titlecompound 54 was prepared according to the method presented for thesynthesis of compound 52 but instead utilizing 112. MS (ESI) m/z 1145.9[M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J=2.2 Hz, 1H),8.19-8.05 (m, 2H), 7.77-7.59 (m, 2H), 7.59-7.51 (m, 1H), 7.44 (d, J=8.2Hz, 2H), 7.39-7.30 (m, 3H), 7.22 (d, J=8.0 Hz, 2H), 7.09 (d, J=10.0 Hz,1H), 7.01-6.88 (m, 2H), 6.77 (d, J=9.9 Hz, 1H), 5.14-5.00 (m, 3H), 4.94(dd, J=8.1, 6.7 Hz, 2H), 4.47 (dd, J=25.9, 10.4 Hz, 3H), 4.37-4.24 (m,1H), 4.14 (d, J=13.0 Hz, 2H), 3.95 (d, J=13.2 Hz, 1H), 3.87-3.57 (m,14H), 2.98-2.67 (m, 4H), 1.25-1.06 (m, 10H), 1.02 (s, 3H).

Example 55

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-8-(4-((6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(55). Intermediates: I2, P4, and S9. MS (ESI) m/z 1129.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.21 (dd, J=2.2, 0.8 Hz, 1H), 8.01 (d, J=2.7Hz, 1H), 7.61 (dd, J=8.9, 2.3 Hz, 1H), 7.44 (t, J=59.6 Hz, 1H), 7.36 (d,J=8.3 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 6.90-6.83(m, 2H), 4.60-4.44 (m, 1H), 4.34 (s, 1H), 4.21 (s, 1H), 4.14-3.98 (m,4H), 3.85 (d, J=13.1 Hz, 1H), 3.76 (t, J=12.6 Hz, 1H), 3.67-3.62 (m,1H), 3.60 (s, 3H), 3.57 (s, 3H), 3.54-3.35 (m, 2H), 2.88-2.73 (m, 4H),2.73-2.66 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s,3H).

Example 56

Methyl((5S,8S,9S,14S)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-11-(4-(pyridin-2-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(56). Intermediates: I2, P30, and S3. MS (ESI) m/z 1081.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.75 (d, J=5.6 Hz, 1H), 8.41 (t, J=8.0 Hz, 1H),8.36-8.25 (m, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.09 (d, J=9.5 Hz, 1H), 7.88(d, J=8.0 Hz, 2H), 7.81 (t, J=6.6 Hz, 1H), 7.74-7.63 (m, 3H), 7.33 (d,J=7.9 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.18 (d, J=9.9 Hz, 1H), 6.86 (d,J=8.9 Hz, 1H), 6.81 (d, J=9.8 Hz, 1H), 4.96 (dd, J=8.1, 7.1 Hz, 2H),4.81 (dd, J=8.2, 5.0 Hz, 2H), 4.44-4.30 (m, 3H), 4.24 (d, J=9.6 Hz, 1H),4.16 (s, 2H), 4.08 (d, J=13.6 Hz, 1H), 3.99 (d, J=13.4 Hz, 1H), 3.76 (s,1H), 3.68 (s, 3H), 3.56 (s, 3H), 3.38 (d, J=13.7 Hz, 2H), 2.98-2.72 (m,3H), 2.27-2.16 (m, 2H), 2.12-2.03 (m, 2H), 1.12 (s, 3H), 1.10 (s, 3H),1.04 (s, 3H), 0.84 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.36,-77.68, -77.89.

Example 57

Methyl((5S,8S,9S,14S)-11-(4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(57). Intermediates: I2, P27, and S3. MS (ESI) m/z 1161.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.29 (d, J=2.3 Hz, 1H), 8.18 (d, J=9.3 Hz, 1H),7.70 (dd, J=8.9, 2.3 Hz, 1H), 7.42-7.31 (m, 4H), 7.22 (d, J=8.1 Hz, 2H),7.17 (d, J=9.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H),6.48 (s, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.85 (s, 2H), 4.81 (dd, J=8.3, 5.0Hz, 2H), 4.47-4.39 (m, 1H), 4.35 (d, J=14.5 Hz, 2H), 4.33-4.26 (m, 1H),4.22-4.07 (m, 9H), 3.93 (d, J=13.3 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H),3.44-3.35 (m, 2H), 2.96-2.71 (m, 4H), 2.27-2.17 (m, 2H), 2.08 (d, J=8.6Hz, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H). ¹⁹F NMR(377 MHz, Methanol-d4) δ -77.40, -77.74, -77.92, -115.37.

Example 58

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(58) (GS-PI1). Intermediates: I2, P4, and S3. MS (ESI) m/z 1155.6[M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.29 (dd, J=2.3, 0.7 Hz, 1H),8.18 (d, J=9.3 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 7.72-7.68 (m, 1H), 7.54(d, J=59.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.22(d, J=8.2 Hz, 2H), 7.15 (d, J=10.0 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.86(d, J=8.9 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H), 4.99-4.92 (m, 2H), 4.84-4.77(m, 2H), 4.44 (d, J=9.9 Hz, 1H), 4.40-4.26 (m, 3H), 4.22-4.09 (m, 4H),3.94 (d, J=13.2 Hz, 1H), 3.78-3.70 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H),3.38 (d, J=13.9 Hz, 2H), 2.95-2.70 (m, 4H), 2.30-2.15 (m, 2H), 2.15-2.03(m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹F NMR(377 MHz, Methanol-d4) δ -77.40, -77.73, -77.90, -96.95 (dd, J=59.9,19.6 Hz), -114.92.

Example 59

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(59). Intermediates: I2, P7, and S34. MS (ESI) m/z 1141.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.8 Hz, 1H), 8.37-8.24 (m, 1H), 8.18(d, J=9.3 Hz, 1H), 8.13 (s, 1H), 7.79 (dd, J=8.6, 2.2 Hz, 1H), 7.51 (t,J=59.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 4H), 7.18 (d,J=9.8 Hz, 1H), 6.82 (d, J=9.8 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 4.77 (t,J=7.6 Hz, 2H), 4.62 (d, J=6.3 Hz, 2H), 4.53 (dd, J=8.3, 5.1 Hz, 2H),4.49-4.41 (m, 1H), 4.37-4.29 (m, 1H), 4.27-4.07 (m, 3H), 3.93 (d, J=13.2Hz, 1H), 3.69 (s, 3H), 3.68-3.61 (m, 4H), 3.00 (dt, J=10.2, 6.3 Hz, 1H),2.94-2.72 (m, 4H), 2.09-1.98 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12(s, 3H), 1.03 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.71,-77.96, -96.87 (d, J=59.7 Hz), -115.01.

Example 60

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(60). Intermediates: I2, P7, and S4. MS (ESI) m/z 1141.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.7 Hz, 1H), 8.37-8.29 (m, 1H), 8.17(d, J=9.4 Hz, 1H), 8.13 (s, 1H), 7.74 (dd, J=8.9, 2.3 Hz, 1H), 7.51 (t,J=59.7 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 7.24 (dd, J=12.7, 8.2 Hz, 4H),7.18 (d, J=10.1 Hz, 1H), 6.84-6.76 (m, 2H), 5.08-4.93 (m, 2H), 4.65-4.56(m, 2H), 4.50-4.41 (m, 1H), 4.39-4.27 (m, 1H), 4.21-4.03 (m, 3H), 3.93(d, J=13.2 Hz, 1H), 3.78-3.68 (m, 4H), 3.67 (s, 3H), 2.95-2.73 (m, 4H),2.11 (d, J=11.1 Hz, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.72, -77.93, -96.87(d, J=59.7 Hz), -115.02

Example 61

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(61). Intermediates: I2, P7, and S7. MS (ESI) m/z 1156.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.7 Hz, 1H), 8.53 (s, 2H), 8.18 (d,J=9.2 Hz, 1H), 8.13 (s, 1H), 7.51 (t, J=59.7 Hz, 1H), 7.34 (d, J=8.2 Hz,2H), 7.24 (t, J=8.1 Hz, 4H), 7.18 (d, J=9.9 Hz, 1H), 6.82 (d, J=9.9 Hz,1H), 5.00-4.92 (m, 2H), 4.84-4.77 (m, 2H), 4.44 (d, J=9.9 Hz, 1H), 4.31(d, J=10.0 Hz, 1H), 4.21-4.07 (m, 3H), 3.79-3.70 (m, 1H), 3.69 (s, 3H),3.66 (s, 3H), 3.52-3.41 (m, 2H), 2.96-2.66 (m, 4H), 2.21 (d, J=11.2 Hz,2H), 1.99 (d, J=9.1 Hz, 2H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H),1.03 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.72, -77.86,-96.87 (d, J=59.7 Hz), -115.03.

Example 62

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(1,5-dimethyl-7-(oxetan-3-yl)-9-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(62) Intermediates: I2, P7, and S37. MS (ESI) m/z 1229.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.8 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H),8.17 (d, J=9.3 Hz, 1H), 8.12 (s, 1H), 7.98-7.88 (m, 1H), 7.58 (t, J=59.7Hz, 1H), 7.38-7.33 (m, 2H), 7.25 (dd, J=8.2, 5.8 Hz, 4H), 7.18 (d, J=9.9Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.83-4.75 (m, 1H), 4.65 (d, J=13.5 Hz,2H), 4.54 (t, J=6.8 Hz, 2H), 4.43 (d, J=9.7 Hz, 1H), 4.35-4.16 (m, 3H),4.13 (t, J=11.3 Hz, 2H), 4.02 (d, J=12.4 Hz, 0H), 3.93 (d, J=13.1 Hz,1H), 3.72 (d, J=10.4 Hz, 2H), 3.69 (d, J=2.1 Hz, 3H), 3.66 (s, 3H),3.53-3.44 (m, 1H), 2.99-2.71 (m, 4H), 2.47 (d, J=11.6 Hz, 2H), 1.17 (s,4H), 1.14 (s, 3H), 1.11 (s, 4H), 1.07 (s, 5H), 1.03 (s, 3H). ¹⁹F NMR(377 MHz, Methanol-d4) δ -77.38, -77.71 (d, J=5.6 Hz), -77.97, -96.87(d, J=59.7 Hz), -115.02.

Example 63

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(63). Intermediates: I2, P9, and S3. MS (ESI) m/z 1119.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 8.09 (d,J=9.7 Hz, 1H), 8.06 (s, 1H), 7.69 (dd, J=8.9, 2.3 Hz, 1H), 7.54 (d,J=8.1 Hz, 2H), 7.48 (t, J=59.9 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.33 (d,J=7.8 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.14 (d, J=9.6 Hz, 1H), 6.86 (d,J=8.9 Hz, 1H), 6.76 (d, J=9.8 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.81 (dd,J=8.3, 5.1 Hz, 2H), 4.45-4.31 (m, 3H), 4.25 (d, J=9.6 Hz, 1H), 4.15 (s,3H), 3.98 (d, J=13.2 Hz, 1H), 3.86 (d, J=13.0 Hz, 1H), 3.74 (d, J=8.3Hz, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 3.37 (d, J=13.9 Hz, 2H), 2.95-2.67(m, 4H), 2.30-2.19 (m, 2H), 2.07 (d, J=8.6 Hz, 2H), 1.12 (s, 3H), 1.09(s, 3H), 1.01 (s, 3H), 0.85 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ-77.41, -77.66, -77.73, -96.57 (d, J=59.9 Hz).

Example 64

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(5,6-difluoropyridin-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(64). Intermediates: I8, and3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. MS(ESI) m/z 1086.21 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.28 (t, J=1.9Hz, 1H), 8.24-8.06 (m, 2H), 7.79 (q, J=8.3 Hz, 2H), 7.42-7.14 (m, 7H),6.99 (t, J=10.5 Hz, 1H), 4.80-4.65 (m, 3H), 4.25-3.84 (m, 10H),3.77-3.58 (m, 9H), 3.19 (t, J=12.3 Hz, 1H), 3.02-2.75 (m, 6H), 2.31-1.76(m, 4H), 0.87 (d, J=27.6 Hz, 20H).

Example 65

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(65). Intermediates: I2, P7, and S41. MS (ESI) m/z 1169.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.38 (s, 1H), 8.14 (d, J=9.5 Hz,1H), 8.12 (s, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.58 (t, J=59.7 Hz, 1H), 7.35(d, J=7.2 Hz, 2H), 7.24 (t, J=7.8 Hz, 4H), 7.14 (d, J=9.8 Hz, 1H), 7.01(d, J=8.9 Hz, 1H), 6.79 (d, J=10.0 Hz, 1H), 4.79 (t, J=7.8 Hz, 2H),4.50-4.24 (m, 5H), 4.19-4.05 (m, 2H), 3.93 (d, J=13.2 Hz, 1H), 3.79-3.63(m, 9H), 3.14 (d, J=12.3 Hz, 2H), 3.00-2.72 (m, 4H), 2.46 (s, 2H),2.13-1.92 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s,3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -77.36, -77.70, -77.78, -96.88 (d,J=59.8 Hz), -115.01.

Example 66

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(66). Intermediates: I2, P7, and S40. MS (ESI) m/z 1190.7 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.52 (d, J=0.7 Hz, 1H), 8.17-8.09 (m, 2H), 7.98(d, J=2.2 Hz, 1H), 7.81 (ddd, J=9.1, 7.0, 1.8 Hz, 1H), 7.76 (ddd, J=6.4,1.8, 0.7 Hz, 1H), 7.57 (dd, J=9.2, 2.3 Hz, 1H), 7.50 (t, J=59.7 Hz, 1H),7.30 (d, J=7.9 Hz, 2H), 7.26-7.18 (m, 5H), 7.13 (d, J=9.9 Hz, 1H), 6.93(d, J=9.3 Hz, 1H), 6.79 (t, J=6.7 Hz, 1H), 4.50 (d, J=13.3 Hz, 2H),4.46-4.38 (m, 1H), 4.24 (d, J=13.1 Hz, 2H), 4.20-4.05 (m, 2H), 3.93 (d,J=13.1 Hz, 1H), 3.77-3.67 (m, 5H), 3.66 (s, 3H), 3.58-3.46 (m, 2H), 3.38(d, J=13.3 Hz, 2H), 2.96-2.71 (m, 4H), 2.35 (s, 2H), 2.14 (t, J=3.2 Hz,2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹F NMR(376 MHz, Methanol-d4) δ -77.34, -77.66, -77.97, -96.87 (d, J=59.6 Hz),-115.00 (d, J=8.7 Hz).

Example 67

Methyl((5S,8S,9S,14S)-8-(4-((6-(7-acetyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(67). Intermediates: I2, P7, and S39. MS (ESI) m/z 1155.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.07 (d, J=9.5 Hz, 1H), 8.03 (s,1H), 7.99 (d, J=2.3 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.49 (t, J=59.7 Hz,1H), 7.26 (d, J=7.9 Hz, 2H), 7.20-7.03 (m, 5H), 6.72 (d, J=10.2 Hz, 1H),4.61 (d, J=13.5 Hz, 1H), 4.38-4.29 (m, 3H), 4.24-4.17 (m, 1H), 4.04 (dt,J=29.4, 13.9 Hz, 5H), 3.83 (d, J=13.1 Hz, 1H), 3.66-3.61 (m, 1H), 3.59(s, 3H), 3.57 (s, 3H), 3.44-3.26 (m, 4H), 2.87-2.62 (m, 6H), 2.11 (s,3H), 1.95 (s, 3H), 1.80 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s,3H), 0.94 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.38, -77.70,-77.88 (TFA peak), -96.88 (d, J=59.8 Hz), -115.02.

Example 68

Methyl((5S,8S,9S,14S)-8-(4-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(68). Intermediates: I2, P7, and S43. MS (ESI) m/z 1100.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.11-8.04 (m, 2H), 8.03 (s, 1H),7.73 (d, J=9.4 Hz, 1H), 7.41 (t, J=59.8 Hz, 1H), 7.26 (d, J=7.2 Hz, 3H),7.15 (t, J=7.6 Hz, 5H), 6.94 (d, J=9.2 Hz, 1H), 4.47-4.38 (m, 2H),4.37-4.30 (m, 1H), 4.24-4.18 (m, 1H), 4.12-3.96 (m, 2H), 3.84 (d, J=13.1Hz, 1H), 3.72 (d, J=12.2 Hz, 2H), 3.66-3.61 (m, 1H), 3.59 (s, 3H), 3.57(s, 3H), 3.18-3.12 (m, 2H), 2.86-2.63 (m, 5H), 1.97-1.85 (m, 2H),1.81-1.73 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.38, -77.70, -77.94, -96.88 (d,J=59.7 Hz), -115.02.

Example 69

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(69). Intermediates: I2, P7, and S5. MS (ESI) m/z 1137.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.09 (d, J=9.4 Hz, 1H), 8.03 (s,1H), 7.73 (s, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.41(d, J=59.7 Hz, 1H), 7.32-7.25 (m, 2H), 7.16 (dd, J=8.3, 3.3 Hz, 4H),7.09 (d, J=9.9 Hz, 1H), 6.71 (d, J=10.0 Hz, 1H), 4.39-4.30 (m, 1H),4.30-4.17 (m, 1H), 4.11-3.97 (m, 2H), 3.84 (d, J=13.2 Hz, 1H), 3.68-3.62(m, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.08 (s, 3H), 2.82 (d, J=7.9 Hz,2H), 2.78-2.61 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.70, -77.82, -96.87(d, J=59.7 Hz), -115.00.

Example 70

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(70). Intermediates: I2, P7, and S38. MS (ESI) m/z 1177.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.12 (s,1H), 7.73 (d, J=9.4 Hz, 1H), 7.50 (d, J=59.7 Hz, 1H), 7.33 (d, J=7.9 Hz,2H), 7.25 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.91 (d, J=9.1 Hz,1H), 4.43 (s, 1H), 4.39 (s, 2H), 4.30 (s, 1H), 4.18-4.01 (m, 4H), 3.93(d, J=13.1 Hz, 1H), 3.76-3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.21(d, J=11.9 Hz, 2H), 3.04 (s, 3H), 2.95-2.70 (m, 4H), 2.12-1.99 (m, 2H),1.86 (t, J=7.0 Hz, 2H), 1.17 (s, 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.40 (d, J=5.6 Hz), -77.71,-77.90, -96.88 (d, J=59.7 Hz), -115.01.

Example 71

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(71). Intermediates: I2, P7, and S3. MS (ESI) m/z 1155.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.24-8.18 (m, 1H), 8.08 (d, J=9.3Hz, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.65-7.52 (m, 3H), 7.50-7.43 (m, 1H),7.41 (d, J=59.7 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H),7.13 (d, J=8.1 Hz, 2H), 6.77 (d, J=8.9 Hz, 1H), 6.71 (d, J=10.0 Hz, 1H),4.87 (t, J=7.6 Hz, 2H), 4.71 (dd, J=8.2, 5.0 Hz, 2H), 4.34 (d, J=9.9 Hz,1H), 4.26 (d, J=13.8 Hz, 2H), 4.21 (d, J=10.0 Hz, 1H), 4.11-3.97 (m,5H), 3.83 (d, J=13.2 Hz, 1H), 3.66-3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s,3H), 3.28 (d, J=13.9 Hz, 2H), 2.85-2.63 (m, 4H), 2.19-2.09 (m, 2H),2.02-1.95 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.40, -77.72, -96.87 (d, J=59.7Hz), -115.02.

Example 72

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(72). Intermediates: I3, P4, and S38. MS (ESI) m/z 1123.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.24-8.14 (m, 2H), 8.10 (d, J=2.7 Hz, 1H), 7.80(dd, J=9.2, 2.3 Hz, 1H), 7.53 (t, J=59.9 Hz, 1H), 7.44 (d, J=8.2 Hz,2H), 7.34 (d, J=8.0 Hz, 2H), 7.28-7.18 (m, 2H), 7.01 (d, J=9.2 Hz, 1H),6.93 (d, J=2.7 Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.47-4.38 (m, 3H),4.17-4.07 (m, 2H), 4.04 (dd, J=12.3, 2.4 Hz, 2H), 3.96 (d, J=13.1 Hz,1H), 3.77-3.72 (m, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.27 (dd, J=12.1,2.5 Hz, 2H), 3.04 (s, 3H), 2.97-2.71 (m, 4H), 2.13-2.04 (m, 2H),1.90-1.81 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0.86 (s, 9H). ¹⁹F NMR(377 MHz, Methanol-d4) δ -77.32, -77.93, -96.91 (dd, J=59.9, 15.2 Hz),-114.77.

Example 73

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(73). Intermediates: I3, P4, and S3. MS (ESI) m/z 1102.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.29 (d, J=2.2 Hz, 1H), 8.17 (d, J=9.4 Hz, 1H),8.10 (d, J=2.7 Hz, 1H), 7.71 (dd, J=8.8, 2.3 Hz, 1H), 7.53 (d, J=59.8Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 6.93 (d, J=2.8 Hz, 1H), 6.91-6.84 (m, 1H), 4.96 (dd, J=8.2, 7.0Hz, 2H), 4.83 (dd, J=8.2, 5.1 Hz, 2H), 4.61-4.49 (m, 1H), 4.43 (s, 1H),4.40-4.29 (m, 2H), 4.19-4.04 (m, 4H), 3.97 (d, J=13.1 Hz, 1H), 3.81-3.72(m, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.41 (dd, J=14.2, 1.7 Hz, 2H),2.99-2.70 (m, 4H), 2.32-2.18 (m, 2H), 2.13-1.99 (m, 2H), 1.14 (s, 3H),1.11 (s, 3H), 0.86 (s, 9H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.35,-78.05 (TFA peak), -96.93 (dd, J=59.7, 14.5 Hz), -114.79.

Example 74

Methyl((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(74). Intermediates: I2, P26, and S3. MS (ESI) m/z 1133.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.71 (d, J=5.2 Hz, 1H), 8.35-8.27 (m, 1H),8.19-8.11 (m, 2H), 8.03 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.70 (dd,J=8.9, 2.3 Hz, 1H), 7.69-7.64 (m, 1H), 7.63-7.57 (m, 1H), 7.33 (d, J=7.9Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.87 (dd, J=9.0, 0.8 Hz, 1H), 4.96 (dd,J=8.2, 7.1 Hz, 2H), 4.82 (dd, J=8.2, 5.1 Hz, 2H), 4.59-4.51 (m, 1H),4.45-4.41 (m, 1H), 4.39-4.24 (m, 5H), 4.20-4.11 (m, 4H), 4.05 (d, J=12.7Hz, 1H), 3.82-3.73 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.44-3.36 (m,2H), 2.92 (t, J=9.0 Hz, 3H), 2.81 (dd, J=12.6, 9.5 Hz, 1H), 2.30-2.18(m, 2H), 2.12-2.04 (m, 2H), 1.14 (s, 6H), 1.12 (s, 3H), 1.00 (s, 3H).¹⁹F NMR (377 MHz, Methanol-d4) δ -77.30, -77.68, -78.09 (TFA peak),-112.80.

Example 75

Methyl((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(75). Intermediates: I2, P3, and S3. MS (ESI) m/z 1163.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.32-8.26 (m, 1H), 8.12 (d, J=9.4 Hz, 1H), 7.70(dd, J=8.8, 2.3 Hz, 1H), 7.51 (d, J=7.5 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),7.22 (d, J=8.0 Hz, 2H), 7.12 (d, J=9.8 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H),6.77 (d, J=9.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.79 (s, 1H), 4.43 (d,J=9.8 Hz, 1H), 4.35 (d, J=14.0 Hz, 2H), 4.28 (d, J=10.0 Hz, 1H), 4.17(s, 5H), 3.97 (d, J=13.2 Hz, 1H), 3.74 (d, J=13.6 Hz, 1H), 3.69 (s, 3H),3.67 (s, 3H), 3.38 (d, J=13.9 Hz, 2H), 3.02-2.84 (m, 3H), 2.82-2.74 (m,1H), 2.53 (td, J=8.6, 4.3 Hz, 1H), 2.27-2.18 (m, 2H), 2.08 (d, J=8.6 Hz,2H), 1.35-1.30 (m, 2H), 1.27 (d, J=16.2 Hz, 0H), 1.20-1.13 (m, 9H), 1.12(s, 3H), 1.03 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -77.31, -77.67,-77.82, -113.25.

Example 76

Methyl((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(76). Intermediates: I3, P3, and S3. MS (ESI) m/z 1110.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.32-8.27 (m, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.70(dd, J=8.7, 2.3 Hz, 1H), 7.51 (d, J=7.5 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H),7.22 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.9 Hz, 1H), 6.78 (s, 0H), 4.96 (t,J=7.6 Hz, 2H), 4.79 (s, 1H), 4.54 (s, 1H), 4.43 (d, J=6.3 Hz, 1H), 4.35(d, J=13.9 Hz, 2H), 4.15 (s, 5H), 3.99 (d, J=13.1 Hz, 1H), 3.74 (s, 1H),3.69 (s, 4H), 3.65 (s, 3H), 3.38 (d, J=13.9 Hz, 2H), 3.34 (s, 1H),3.00-2.75 (m, 2H), 2.51 (dq, J=8.5, 4.9, 4.3 Hz, 1H), 2.27-2.18 (m, 2H),2.08 (d, J=8.6 Hz, 2H), 1.36-1.30 (m, 2H), 1.19-1.13 (m, 6H), 1.12 (s,3H), 0.85 (s, 10H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -77.28, -77.92,-113.11.

Example 77

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(77). Intermediates: I3, P1, and S3. MS (ESI) m/z 1102.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.30 (d, J=2.1 Hz, 1H), 8.15 (s, 1H), 8.00 (s,1H), 7.74-7.66 (m, 1H), 7.57 (s, 1H), 7.42 (s, 0H), 7.39 (d, J=8.4 Hz,2H), 7.32 (d, J=7.8 Hz, 2H), 7.21 (d, J=8.0 Hz, 3H), 6.86 (d, J=8.9 Hz,1H), 4.97 (t, J=7.6 Hz, 3H), 4.80 (d, J=5.2 Hz, 1H), 4.43 (d, J=9.8 Hz,1H), 4.35 (d, J=14.1 Hz, 2H), 4.19-4.08 (m, 5H), 3.96 (d, J=13.2 Hz,1H), 3.76 (s, 1H), 3.69 (s, 4H), 3.65 (s, 3H), 3.38 (d, J=13.9 Hz, 3H),2.90 (d, J=8.1 Hz, 2H), 2.81 (s, 1H), 2.22 (s, 2H), 2.08 (d, J=8.7 Hz,2H), 1.13 (d, J=14.1 Hz, 8H), 0.86 (s, 12H). ¹⁹F NMR (376 MHz,Methanol-d4) δ -77.36, -77.93, -94.99 (d, J=60.0 Hz), -115.00

Example 78

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(78). Intermediates: I2, P28, and S45. MS (ESI) m/z 1131.0 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.65 (d, J=5.0 Hz, 1H), 8.14 (d, J=9.3 Hz,1H), 7.98-7.85 (m, 2H), 7.61 (t, J=8.1 Hz, 3H), 7.47-7.38 (m, 1H), 7.33(d, J=7.8 Hz, 3H), 7.22 (d, J=8.0 Hz, 2H), 7.09 (d, J=9.9 Hz, 1H), 6.77(d, J=9.8 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.42(dd, J=25.4, 11.7 Hz, 2H), 4.33-4.27 (m, 1H), 4.22-4.10 (m, 4H), 3.98(d, J=13.0 Hz, 1H), 3.73 (s, 1H), 3.68 (s, 4H), 3.63 (s, 3H), 3.35 (d,J=14.0 Hz, 2H), 2.97-2.86 (m, 3H), 2.84-2.75 (m, 1H), 2.56 (s, 4H),2.25-2.16 (m, 2H), 2.13-2.01 (m, 2H), 1.28 (d, J=8.8 Hz, 0H), 1.16 (d,J=2.7 Hz, 7H), 1.13 (s, 4H), 1.03 (s, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ -77.35, -77.68, -114.72.

Example 79

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(79). Intermediates: I2, P1, and S3. MS (ESI) m/z 1156.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.32-8.28 (m, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.13(s, 0H), 8.00 (d, J=1.3 Hz, 1H), 7.73 (s, 0H), 7.70 (dd, J=8.8, 2.3 Hz,1H), 7.58 (s, 1H), 7.43 (s, 0H), 7.39 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.8Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.12 (d, J=9.8 Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 6.77 (d, J=10.0 Hz, 0H), 4.97 (t, J=7.6 Hz, 2H), 4.82-4.78 (m,2H), 4.53 (s, 1H), 4.44 (d, J=6.5 Hz, 1H), 4.39-4.28 (m, 3H), 4.13 (d,J=15.7 Hz, 4H), 3.94 (d, J=13.3 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H),3.38 (d, J=13.9 Hz, 2H), 2.97-2.72 (m, 6H), 2.27-2.19 (m, 2H), 2.08 (d,J=8.6 Hz, 2H), 1.21 (t, J=7.3 Hz, 4H), 1.16 (d, J=8.4 Hz, 6H), 1.11 (s,3H), 1.03 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -74.51, -76.39,-77.39, -77.71, -77.89, -94.98 (d, J=60.0 Hz), -97.37 (d, J=59.1 Hz),-115.13

Example 80

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(80). Intermediates: I6, P7, and S3. MS (ESI) m/z 1119.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.54 (d, J=0.7 Hz, 1H), 8.32-8.27 (m, 1H), 8.17(d, J=9.4 Hz, 1H), 8.12 (s, 1H), 7.88-7.73 (m, 0H), 7.70 (dd, J=8.8, 2.3Hz, 1H), 7.65 (s, 0H), 7.51 (s, 1H), 7.38-7.30 (m, 2H), 7.24 (dd,J=16.7, 8.2 Hz, 4H), 6.86 (d, J=9.0 Hz, 1H), 6.81 (d, J=9.9 Hz, 1H),4.96 (dd, J=8.1, 7.0 Hz, 2H), 4.84-4.77 (m, 2H), 4.47-4.41 (m, 1H), 4.36(d, J=13.7 Hz, 2H), 4.22 (d, J=9.2 Hz, 1H), 4.18-4.03 (m, 5H), 4.00 (s,1H), 3.98-3.91 (m, 2H), 3.71 (s, 0H), 3.69 (s, 3H), 3.66 (s, 3H), 3.37(d, J=13.8 Hz, 2H), 3.04 (q, J=7.4 Hz, 1H), 2.99 (d, J=0.5 Hz, 0H), 2.90(d, J=9.1 Hz, 2H), 2.86 (d, J=0.7 Hz, 0H), 2.79 (d, J=9.6 Hz, 2H),2.28-2.19 (m, 2H), 2.11-2.02 (m, 2H), 1.29 (t, J=7.3 Hz, 1H), 1.13 (d,J=10.8 Hz, 6H), 1.02 (t, J=7.4 Hz, 0H), 0.93-0.84 (m, 6H). ¹⁹F NMR (377MHz, Methanol-d4) δ -77.38, -77.88, -96.88 (d, J=59.7 Hz), -114.92

Example 81

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(81). Intermediates: I2, P4, and S47. MS (ESI) m/z 1102.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.25-8.21 (m, 1H), 8.16 (d, J=9.3 Hz, 1H), 8.10(d, J=2.8 Hz, 1H), 7.77 (dd, J=9.0, 2.3 Hz, 1H), 7.53 (s, 1H), 7.45 (d,J=8.2 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.13 (d,J=9.9 Hz, 1H), 6.98-6.91 (m, 2H), 6.80 (d, J=9.9 Hz, 1H), 4.48-4.41 (m,1H), 4.36-4.27 (m, 1H), 4.20 (s, 2H), 4.14 (d, J=13.0 Hz, 2H), 3.96 (s,1H), 3.95-3.87 (m, 3H), 3.73 (s, 2H), 3.68 (d, J=11.7 Hz, 6H), 3.60-3.51(m, 2H), 3.04 (s, 3H), 2.94-2.84 (m, 3H), 2.84-2.73 (m, 1H), 1.20-1.08(m, 9H), 1.03 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71,-96.96 (dd, J=59.8, 19.5 Hz), -114.92.

Example 82

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(82). Intermediates: I2, P33, and S3. MS (ESI) m/z 1123.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.30 (dd, J=2.4, 0.7 Hz, 1H), 8.16 (d, J=9.4Hz, 1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.21 (d,J=8.3 Hz, 2H), 6.92-6.71 (m, 3H), 4.97 (dd, J=8.1, 7.2 Hz, 2H),4.83-4.74 (m, 2H), 4.58-4.23 (m, 4H), 4.17-3.96 (m, 8H), 3.90 (d, J=13.4Hz, 1H), 3.74-3.58 (m, 8H), 3.54 (td, J=11.2, 3.9 Hz, 2H), 3.39 (d,J=13.8 Hz, 2H), 3.03-2.60 (m, 5H), 2.36-2.17 (m, 2H), 2.20-2.03 (m, 4H),1.93-1.83 (m, 1H), 1.80-1.48 (m, 5H), 1.29 (d, J=3.8 Hz, 1H), 1.20-1.05(m, 11H), 0.95 (d, J=41.7 Hz, 4H).

Example 83

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(oxetan-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(83). Intermediates: I2, P32, and S3. MS (ESI) m/z 1095.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) 6 8.28 (dd, J=2.3, 0.7 Hz, 1H), 8.15 (d, J=9.4Hz, 1H), 7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.20 (d,J=8.1 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 6.92-6.70 (m, 2H), 5.05 (dd,J=8.3, 6.1 Hz, 3H), 4.95 (dd, J=8.2, 7.0 Hz, 3H), 4.80 (dd, J=8.0, 4.8Hz, 3H), 4.67 (t, J=6.3 Hz, 2H), 4.50-4.17 (m, 4H), 4.14 (d, J=4.3 Hz,3H), 3.68 (d, J=1.5 Hz, 7H), 3.38 (dd, J=14.2, 1.7 Hz, 3H), 3.00-2.68(m, 2H), 2.06 (d, J=9.0 Hz, 1H), 1.73 (d, J=7.2 Hz, 0H), 1.64-1.49 (m,1H), 1.42-1.25 (m, 25H), 1.17-1.05 (m, 11H), 1.01 (s, 3H), 0.96 (d,J=6.6 Hz, 2H), 0.92-0.80 (m, 24H).

Example 84

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(84). Intermediates: I1, P28, and S3. MS (ESI) m/z 1009.35 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.65 (d, J=4.9 Hz, 1H), 8.34-8.25 (m, 1H),8.01-7.87 (m, 2H), 7.83 (d, J=9.4 Hz, 1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H),7.59 (d, J=8.6 Hz, 2H), 7.44 (dd, J=7.0, 5.0 Hz, 1H), 7.33 (d, J=7.8 Hz,2H), 7.24 (d, J=7.9 Hz, 2H), 6.86 (d, J=8.7 Hz, 1H), 4.96 (t, J=7.6 Hz,2H), 4.84-4.79 (m, 1H), 4.53 (s, 1H), 4.35 (d, J=13.9 Hz, 2H), 4.15 (s,6H), 4.00 (d, J=13.1 Hz, 1H), 3.90 (s, 1H), 3.80-3.58 (m, 9H), 3.40 (s,1H), 3.03-2.80 (m, 5H), 2.34-2.20 (m, 3H), 2.07 (d, J=8.6 Hz, 2H), 0.87(d, J=24.4 Hz, 19H).

Example 85

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(85). Intermediates: I3, P6, and S3. MS (ESI) m/z 1066.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.25 (d, J=2.3 Hz, 1H), 8.13-8.04 (m, 2H),7.83-7.74 (m, 4H), 7.47 (d, J=8.2 Hz, 3H), 7.35-7.30 (m, 3H), 7.23 (d,J=8.2 Hz, 3H), 6.99 (d, J=9.1 Hz, 2H), 6.86 (d, J=2.7 Hz, 1H), 4.58-4.49(m, 2H), 4.35 (t, J=4.9 Hz, 1H), 4.31-4.23 (m, 3H), 4.17 (d, J=3.8 Hz,3H), 4.03-3.89 (m, 2H), 3.81 (s, 1H), 3.67 (s, 5H), 3.62-3.49 (m, 6H),2.95-2.74 (m, 3H), 2.30-2.23 (m, 2H), 2.07 (d, J=8.8 Hz, 2H), 1.02 (d,J=34.0 Hz, 6H), 0.74 (s, 10H). ¹⁹NMR (377 MHz, Methanol-d₄) δ -77.58,-96.21 (d, J=59.7 Hz).

Example 86

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(86) Intermediates: I3, P7, and S3. MS (ESI) m/z 1066.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.53 (d, J=0.7 Hz, 1H), 8.16 (d, J=9.3 Hz, 1H),8.11 (d, J=0.6 Hz, 1H), 7.72-7.69 (m, 1H), 7.37-7.30 (m, 3H), 7.27-7.19(m, 5H), 6.87 (dd, J=9.1, 0.8 Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.98-4.94(m, 2H), 4.84-4.81 (m, 2H), 4.46-4.41 (m, 1H), 4.38-4.31 (m, 2H),4.18-4.07 (m, 5H), 3.95 (d, J=13.2 Hz, 1H), 3.76 (s, 1H), 3.67 (d,J=15.6 Hz, 7H), 3.40 (dd, J=14.2, 1.8 Hz, 2H), 2.93-2.87 (m, 2H), 2.80(s, 2H), 2.26-2.20 (m, 2H), 2.10-2.04 (m, 2H), 1.13 (d, J=11.9 Hz, 7H),0.86 (s, 11H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ -78.10, -96.87 (d,J=59.7 Hz), -114.89.

Example 87

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(87). Intermediates: I2, P4, and S49. MS (ESI) m/z 1130.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.20-8.01 (m, 1H), 7.67 (s, 0H),7.52 (s, 0H), 7.44 (d, J=8.2 Hz, 1H), 7.40-7.29 (m, 1H), 7.23 (d, J=8.2Hz, 1H), 7.09 (d, J=9.9 Hz, 0H), 6.93 (d, J=2.8 Hz, 1H), 6.77 (d, J=9.9Hz, 0H), 4.90 (t, J=7.7 Hz, 1H), 4.52-4.27 (m, 2H), 4.14 (d, J=13.5 Hz,2H), 3.94 (d, J=13.1 Hz, 1H), 3.67 (d, J=10.3 Hz, 4H), 2.98-2.72 (m,2H), 1.28-1.06 (m, 5H), 1.02 (s, 1H).

Example 88

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(88). Intermediates: I2, P16, and S49. MS (ESI) m/z 1092.9 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.86 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 8.14(d, J=9.3 Hz, 0H), 7.97 (d, J=8.6 Hz, 1H), 7.40 (t, J=4.9 Hz, 1H), 7.34(d, J=7.9 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.08 (d, J=10.0 Hz, 0H), 6.78(d, J=9.9 Hz, 0H), 4.90 (t, J=7.7 Hz, 1H), 4.51-4.26 (m, 2H), 4.25-4.09(m, 2H), 3.98 (d, J=13.2 Hz, 1H), 3.67 (d, J=8.1 Hz, 3H), 3.26 (s, 2H),2.99-2.75 (m, 2H), 2.02 (s, 0H), 1.24-1.07 (m, 5H), 1.02 (s, 1H).

Example 89

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(89). Intermediates: I2, P16, and S7. MS (ESI) m/z 1119.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.86 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 8.15 (d,J=9.4 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.40 (t, J=4.9 Hz, 1H), 7.34 (d,J=7.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.09 (d, J=9.9 Hz, 0H), 6.78 (d,J=9.9 Hz, 0H), 4.96 (t, J=7.6 Hz, 1H), 4.82-4.70 (m, 2H), 4.43 (d, J=9.9Hz, 0H), 4.30 (d, J=10.0 Hz, 1H), 4.24-4.06 (m, 2H), 3.98 (d, J=13.1 Hz,1H), 3.68 (d, J=8.7 Hz, 4H), 3.46 (d, J=14.7 Hz, 1H), 2.99-2.70 (m, 2H),2.27-2.10 (m, 1H), 1.99 (d, J=8.7 Hz, 1H), 1.19-1.05 (m, 5H), 1.02 (s,2H).

Example 90

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(90). Intermediates: I3, P13, and S6. MS (ESI) m/z 1078.1 [M+H]⁺. 1H NMR(400 MHz, Methanol-d4) δ 8.25 (d, J=2.2 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H),7.70 (dd, J=11.1, 2.3 Hz, 2H), 7.43-7.27 (m, 4H), 7.21 (d, J=7.9 Hz,2H), 6.77 (d, J=9.9 Hz, 0H), 6.73-6.58 (m, 2H), 5.05 (s, 1H), 5.00-4.88(m, 2H), 4.71 (dd, J=8.4, 4.6 Hz, 1H), 4.64-4.54 (m, 2H), 4.47 (d,J=31.7 Hz, 2H), 4.10 (d, J=13.2 Hz, 2H), 3.95 (d, J=13.2 Hz, 1H),3.82-3.56 (m, 13H), 3.33 (s, 1H), 2.89 (d, J=8.9 Hz, 2H), 2.33 (s, 2H),1.21-0.99 (m, 11H), 0.86 (s, 10H).

Example 91

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(91). Intermediates: I3, P13, and S48. MS (ESI) m/z 1066.6 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.30 (d, J=2.2 Hz, 1H), 8.15 (d, J=9.4 Hz,1H), 7.79-7.63 (m, 2H), 7.33 (dd, J=8.2, 5.2 Hz, 4H), 7.21 (d, J=8.0 Hz,2H), 6.95 (d, J=8.9 Hz, 1H), 6.77 (d, J=10.0 Hz, 1H), 6.63 (d, J=2.4 Hz,1H), 4.91 (t, J=7.7 Hz, 2H), 4.54-4.33 (m, 2H), 4.18-4.02 (m, 2H),4.03-3.85 (m, 5H), 3.83-3.58 (m, 10H), 2.89 (d, J=9.3 Hz, 2H), 1.27 (d,J=13.9 Hz, 1H), 1.21-1.00 (m, 12H), 0.86 (s, 10H).

Example 92

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(92). Intermediates: I2, P13, and S48. MS (ESI) m/z 1119.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.29 (d, J=2.2 Hz, 1H), 8.14 (d, J=9.4 Hz,1H), 7.70 (dd, J=9.2, 2.3 Hz, 2H), 7.64-7.51 (m, 0H), 7.33 (dd, J=8.4,4.0 Hz, 5H), 7.21 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.8 Hz, 1H), 6.94 (d,J=8.9 Hz, 1H), 6.76 (d, J=10.0 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 5.48 (s,1H), 4.91 (dd, J=8.3, 7.0 Hz, 3H), 4.51-4.38 (m, 2H), 4.31 (d, J=9.9 Hz,1H), 4.13 (dd, J=15.3, 11.1 Hz, 3H), 3.93 (d, J=13.0 Hz, 2H), 3.79-3.62(m, 10H), 3.58-3.43 (m, 0H), 2.99-2.66 (m, 5H), 1.27 (d, J=13.9 Hz, 1H),1.21-0.97 (m, 19H).

Example 93

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(93). Intermediates: I2, P16, and S6. MS (ESI) m/z 1103.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.86 (d, J=4.8 Hz, 1H), 8.28-8.20 (m, 0H), 8.14(d, J=9.4 Hz, 0H), 7.96 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8, 2.3 Hz, 1H),7.40 (t, J=4.9 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H),6.74-6.65 (m, 1H), 5.05 (d, J=2.0 Hz, 1H), 5.01-4.90 (m, 1H), 4.72 (dd,J=8.4, 4.8 Hz, 1H), 4.58-4.49 (m, 1H), 4.43 (t, J=5.0 Hz, 0H), 4.40-4.26(m, 1H), 4.18 (d, J=12.8 Hz, 1H), 3.98 (d, J=13.1 Hz, 1H), 3.87-3.63 (m,5H), 3.34 (s, 0H), 3.03-2.75 (m, 2H), 2.33 (s, 1H), 1.13 (d, J=14.3 Hz,5H), 1.02 (s, 2H).

Example 94

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(94). Intermediates: I3, P16, and S48. MS (ESI) m/z 1037.6 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.86 (d, J=4.8 Hz, 1H), 8.29 (d, J=2.2 Hz,0H), 7.97 (d, J=8.9 Hz, 1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (t,J=4.9 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.95 (d,J=8.9 Hz, 1H), 6.77 (d, J=9.9 Hz, 0H), 4.84 (s, 15H), 4.57-4.31 (m, 1H),4.16 (d, J=14.1 Hz, 1H), 3.98 (d, J=35.4 Hz, 2H), 3.76 (s, 1H), 3.67 (d,J=14.2 Hz, 4H), 3.04-2.69 (m, 2H), 2.02 (s, 1H), 1.27 (d, J=13.9 Hz,1H), 1.12 (d, J=14.5 Hz, 3H), 0.85 (s, 5H).

Example 95

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(95). Intermediates: I3, P16, and S6. MS (ESI) m/z 1050.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.86 (d, J=4.9 Hz, 1H), 8.24 (d, J=2.1 Hz, 0H),8.15 (d, J=9.3 Hz, 0H), 7.97 (d, J=8.7 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz,1H), 7.39 (t, J=4.9 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.9 Hz,1H), 6.78 (d, J=9.8 Hz, 0H), 6.67 (d, J=8.8 Hz, 1H), 5.05 (s, 0H),4.98-4.85 (m, 1H), 4.71 (dd, J=8.4, 4.7 Hz, 1H), 4.66-4.55 (m, 1H),4.53-4.41 (m, 1H), 4.16 (d, J=13.7 Hz, 1H), 4.00 (d, J=13.1 Hz, 1H),3.87-3.61 (m, 6H), 3.30 (p, J=1.6 Hz, 4H), 3.00-2.74 (m, 2H), 2.33 (s,1H), 1.12 (d, J=14.5 Hz, 3H), 0.85 (s, 5H).

Example 96

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(96). Intermediates: I3, P16, and S3. MS (ESI) m/z 1063.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.86 (dd, J=4.9, 0.8 Hz, 1H), 8.29 (d, J=2.2Hz, 0H), 8.15 (d, J=9.4 Hz, 0H), 7.97 (d, J=8.6 Hz, 1H), 7.69 (dd,J=8.9, 2.3 Hz, 1H), 7.40 (t, J=4.9 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.21(d, J=8.0 Hz, 1H), 6.85 (d, J=8.9 Hz, 1H), 6.77 (d, J=10.0 Hz, 0H), 4.96(t, J=7.6 Hz, 1H), 4.83 (s, 20H), 4.39 (dd, J=34.8, 11.8 Hz, 2H), 4.16(d, J=14.7 Hz, 2H), 4.01 (d, J=13.1 Hz, 1H), 3.84-3.60 (m, 4H), 3.37 (d,J=13.9 Hz, 1H), 3.01-2.73 (m, 2H), 2.33-2.17 (m, 1H), 2.07 (d, J=8.6 Hz,1H), 1.12 (d, J=14.3 Hz, 3H), 0.85 (s, 5H).

Example 97

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(97). Intermediates: I2, P14, and S48. MS (ESI) m/z 1108.4 [M+H]⁺. 1HNMR (400 MHz, Methanol-d4) δ 8.54 (d, J=2.9 Hz, 1H), 8.29 (d, J=2.2 Hz,1H), 8.14 (d, J=9.3 Hz, 1H), 7.95 (dd, J=8.9, 4.2 Hz, 1H), 7.78-7.51 (m,4H), 7.32 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.11 (d, J=10.0 Hz,1H), 6.94 (d, J=8.9 Hz, 1H), 6.77 (d, J=9.9 Hz, 1H), 4.83 (s, 46H),4.52-4.25 (m, 3H), 4.16 (d, J=13.4 Hz, 2H), 3.96 (d, J=13.1 Hz, 1H),3.67 (d, J=15.7 Hz, 7H), 3.26 (s, 5H), 2.97-2.72 (m, 4H), 2.02 (s, 2H),1.28-1.08 (m, 10H), 1.02 (s, 3H).

Example 98

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(98). Intermediates: I2, P15, and S48. MS (ESI) m/z 1109.1 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.66 (dd, J=8.6, 5.6 Hz, 1H), 8.34-8.27 (m,1H), 8.16 (d, J=9.3 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.80-7.61 (m, 4H),7.61-7.48 (m, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.28-7.17 (m, 3H), 7.14 (d,J=9.8 Hz, 1H), 6.99-6.92 (m, 1H), 6.79 (d, J=10.0 Hz, 1H), 4.86 (s,32H), 4.54-4.39 (m, 2H), 4.35-4.26 (m, 1H), 4.17 (d, J=13.1 Hz, 2H),3.95 (t, J=17.4 Hz, 4H), 3.67 (d, J=16.6 Hz, 7H), 2.98-2.73 (m, 4H),1.28 (d, J=13.9 Hz, 5H), 1.20-1.08 (m, 10H), 1.03 (s, 3H).

Example 99

Methyl((5S,8S,9S,14S)-11-(4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(99). Intermediates: I2, P35, and S3. MS (ESI) m/z 1167.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.15 (d, J=9.4 Hz, 1H), 8.10-8.00 (m, 3H),7.72-7.60 (m, 4H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.11(d, J=18.4 Hz, 1H), 6.88-6.75 (m, 3H), 4.96 (t, J=7.6 Hz, 2H), 4.80 (d,J=5.0 Hz, 1H), 4.54 (s, 1H), 4.47-4.42 (m, 1H), 4.33 (dd, J=16.8, 11.9Hz, 4H), 4.20-4.12 (m, 4H), 3.98 (d, J=13.1 Hz, 1H), 3.67 (d, J=17.6 Hz,8H), 3.39 (d, J=13.7 Hz, 2H), 2.90 (dd, J=10.5, 7.0 Hz, 3H), 2.84-2.77(m, 1H), 2.27-2.19 (m, 2H), 2.11-2.04 (m, 2H), 1.18-1.11 (m, 9H), 1.03(s, 3H).

Example 100

Methyl((5S,8S,9S,14S)-11-(4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(100). Intermediates: I2, P45, and S3. MS (ESI) m/z 1165.0 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.91 (d, J=1.8 Hz, 1H), 8.31-8.22 (m, 2H),7.79 (d, J=8.2 Hz, 1H), 7.73-7.61 (m, 2H), 7.34 (dd, J=8.2, 3.3 Hz, 4H),7.25-7.15 (m, 3H), 6.93-6.84 (m, 2H), 6.77 (s, 1H), 4.96 (t, J=7.6 Hz,2H), 4.82-4.79 (m, 2H), 4.54 (s, 1H), 4.38-4.28 (m, 4H), 4.16 (s, 4H),3.98 (d, J=13.2 Hz, 1H), 3.67 (d, J=21.9 Hz, 7H), 3.39 (d, J=13.8 Hz,2H), 2.96-2.76 (m, 5H), 2.28-2.20 (m, 2H), 2.12-2.04 (m, 2H), 1.23-1.12(m, 9H), 1.04 (s, 3H).

Example 101

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(101). Intermediates: I2, P16, and S3. MS (ESI) m/z 1116.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.87 (dd, J=4.9, 4.1 Hz, 2H), 8.32-8.27 (m,1H), 8.15 (d, J=9.3 Hz, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.70 (dd, J=8.8,2.3 Hz, 1H), 7.44-7.29 (m, 4H), 7.24 (t, J=9.4 Hz, 2H), 7.07 (t, J=13.8Hz, 1H), 6.81 (dd, J=34.9, 9.4 Hz, 2H), 4.96 (t, J=7.6 Hz, 2H),4.82-4.78 (m, 2H), 4.61-4.41 (m, 3H), 4.33 (dd, J=18.6, 12.0 Hz, 4H),4.16 (s, 4H), 3.99 (d, J=13.1 Hz, 1H), 3.68 (d, J=8.8 Hz, 6H), 3.41-3.35(m, 2H), 2.95-2.76 (m, 4H), 2.27-2.20 (m, 2H), 2.08 (d, J=8.7 Hz, 2H),1.15 (dd, J=14.6, 11.3 Hz, 9H), 1.03 (s, 3H).

Example 102

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(102). Intermediates: I2, P14, and S3. MS (ESI) m/z 1135.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.54 (d, J=2.9 Hz, 1H), 7.97-7.94 (m, 1H),7.70-7.53 (m, 12H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.86(d, J=8.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.84-4.81 (m, 1H), 4.54 (s,1H), 4.44 (t, J=5.0 Hz, 1H), 4.38-4.29 (m, 3H), 4.15 (d, J=5.9 Hz, 4H),3.98 (s, 1H), 3.67 (d, J=15.3 Hz, 8H), 3.44-3.37 (m, 2H), 2.92-2.74 (m,4H), 2.23 (dd, J=9.6, 4.5 Hz, 2H), 2.12-2.03 (m, 2H), 1.18-1.10 (m, 8H),1.03 (s, 3H).

Example 103

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(103). Intermediates: I2, P7, and S49. MS (ESI) m/z 1130.9 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.53 (d, J=4.0 Hz, 3H), 8.19-8.11 (m, 3H),7.38-7.32 (m, 3H), 7.24 (t, J=8.0 Hz, 5H), 7.16 (d, J=9.9 Hz, 1H), 4.90(t, J=7.6 Hz, 3H), 4.83-4.78 (m, 1H), 4.48-4.36 (m, 3H), 4.31 (d, J=10.0Hz, 1H), 4.17-4.08 (m, 4H), 3.93 (d, J=13.3 Hz, 1H), 3.67 (d, J=9.7 Hz,9H), 2.93-2.72 (m, 6H), 1.19-1.09 (m, 11H), 1.03 (s, 3H).

Example 104

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(104). Intermediates: I2, P4, and S50. MS (ESI) m/z 1158.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.31-8.29 (m, 1H), 8.16 (d, J=9.4 Hz, 1H),8.10 (d, J=2.7 Hz, 1H), 7.73-7.61 (m, 2H), 7.45 (d, J=8.3 Hz, 3H), 7.33(d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 3H), 6.94 (dd, J=5.7, 3.0 Hz, 2H),4.30 (d, J=9.9 Hz, 1H), 4.19-4.06 (m, 5H), 3.95 (d, J=13.2 Hz, 1H), 3.68(d, J=11.0 Hz, 10H), 3.47 (ddd, J=24.1, 12.1, 9.2 Hz, 5H), 2.93-2.74 (m,5H), 2.11 (d, J=10.4 Hz, 3H), 1.77 (qd, J=12.1, 4.6 Hz, 3H), 1.18-1.10(m, 10H), 1.03 (s, 3H).

Example 105

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(105). Intermediates: I3, P14, and S3. MS (ESI) m/z 1081.1 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.54 (d, J=2.9 Hz, 1H), 8.29 (d, J=2.2 Hz,1H), 8.15 (d, J=9.4 Hz, 1H), 7.95 (dd, J=8.9, 4.2 Hz, 1H), 7.76-7.64 (m,2H), 7.60 (d, J=8.7 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.21 (d, J=8.0 Hz,2H), 6.94-6.80 (m, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.85 (s, 14H), 4.54 (s,1H), 4.43 (s, 1H), 4.39-4.28 (m, 2H), 4.18-4.09 (m, 4H), 3.99 (d, J=13.0Hz, 1H), 3.82-3.58 (m, 8H), 3.41-3.33 (m, 2H), 3.00-2.71 (m, 4H), 2.23(dd, J=9.8, 4.6 Hz, 2H), 2.14-2.01 (m, 2H), 1.13 (d, J=12.5 Hz, 6H),0.86 (s, 9H).

Example 106

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(106). Intermediates: I3, P36, and S45. MS (ESI) m/z 1078.8 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.71 (s, 1H), 8.16 (d, J=9.4 Hz, 1H), 7.72(d, J=8.3 Hz, 2H), 7.62 (d, J=8.7 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.24(s, 0H), 6.81 (d, J=9.9 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.96 (t, J=7.6Hz, 2H), 4.54 (s, 1H), 4.50-4.30 (m, 3H), 4.15 (t, J=10.1 Hz, 4H), 4.01(d, J=13.1 Hz, 1H), 3.81-3.55 (m, 7H), 3.37 (d, J=13.8 Hz, 2H),3.00-2.74 (m, 4H), 2.56 (s, 3H), 2.22 (dd, J=9.6, 4.4 Hz, 2H), 2.13-1.97(m, 2H), 1.14 (d, J=10.5 Hz, 6H), 0.85 (s, 9H).

Example 107

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrazin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(107). Intermediates: I3, P36, and S3. MS (ESI) m/z 1064.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 9.15 (s, 1H), 8.59 (s, 1H), 8.32-8.26 (m,1H), 7.76-7.66 (m, 3H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H),6.89-6.84 (m, 1H), 6.79 (d, J=9.8 Hz, 1H), 4.96 (t, J=7.6 Hz, 3H),4.84-4.79 (m, 3H), 4.54 (s, 1H), 4.44 (d, J=6.5 Hz, 1H), 4.39-4.31 (m,2H), 4.16 (d, J=4.9 Hz, 4H), 4.01 (d, J=13.1 Hz, 1H), 3.78-3.63 (m, 9H),3.43-3.36 (m, 2H), 2.94-2.77 (m, 5H), 2.27-2.19 (m, 2H), 2.11-2.04 (m,2H), 1.13 (d, J=10.7 Hz, 6H), 0.86 (s, 9H).

Example 108

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(108). Intermediates: I2, P7, and S56. ¹H NMR (400 MHz, Methanol-d₄) δ8.52 (d, J=0.7 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 2H),7.75-7.61 (m, 2H), 7.57-7.46 (m, 1H), 7.39-7.30 (m, 2H), 7.23 (dd,J=10.8, 8.2 Hz, 4H), 7.12 (d, J=9.9 Hz, 1H), 6.80 (dd, J=31.1, 9.4 Hz,2H), 4.61 (d, J=6.3 Hz, 2H), 4.50-4.36 (m, 3H), 4.30-4.23 (m, 3H), 4.12(d, J=12.2 Hz, 3H), 3.93 (d, J=13.2 Hz, 1H), 3.81 (d, J=11.0 Hz, 0H),3.68 (d, J=10.0 Hz, 6H), 3.56 (s, 1H), 3.45 (d, J=14.1 Hz, 1H),2.98-2.64 (m, 4H), 2.38 (d, J=11.2 Hz, 2H), 2.19-2.05 (m, 2H), 1.62 (s,2H), 1.22-1.08 (m, 9H), 1.00 (d, J=26.6 Hz, 4H).

Example 109

Methyl((5S,8S,9S,14S)-8-(4-((6-(8-(azetidin-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(109) Intermediates: I2, P7, and S51 followed by treatment withtrifluoroacetic acid to remove the Boc-group. MS (ESI) m/z 1169.0[M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.51 (d, J=0.7 Hz, 1H), 8.11 (s,2H), 7.70 (dd, J=8.9, 2.3 Hz, 1H), 7.35-7.31 (m, 2H), 7.26-7.20 (m, 4H),6.87-6.84 (m, 1H), 4.44 (d, J=6.5 Hz, 1H), 4.33-4.22 (m, 6H), 4.19-4.04(m, 7H), 3.93 (d, J=13.2 Hz, 1H), 3.68 (d, J=9.4 Hz, 9H), 3.54 (s, 3H),3.43 (d, J=13.7 Hz, 3H), 2.93-2.73 (m, 5H), 2.28 (dd, J=8.6, 3.7 Hz,2H), 2.13-2.05 (m, 2H), 1.19-1.10 (m, 9H), 1.04 (s, 3H).

Example 110

tert-butyl3-((3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)azetidine-1-carboxylate(110). Intermediates: I2, P7, and S51. MS (ESI) m/z 1268.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.51 (d, J=0.7 Hz, 1H), 8.11 (s, 2H), 7.70(dd, J=8.9, 2.3 Hz, 1H), 7.35-7.31 (m, 2H), 7.26-7.19 (m, 4H), 6.88-6.84(m, 1H), 4.44 (d, J=6.5 Hz, 1H), 4.33-4.22 (m, 6H), 4.19-4.05 (m, 7H),3.93 (d, J=13.2 Hz, 2H), 3.68 (d, J=9.4 Hz, 16H), 3.54 (s, 3H), 3.43 (d,J=13.7 Hz, 2H), 2.94-2.74 (m, 6H), 2.28 (dd, J=8.6, 3.7 Hz, 2H),2.12-2.06 (m, 2H), 1.18-1.10 (m, 9H), 1.04 (s, 3H).

Example 111

Methyl((5S,8S,9S,14S)-16,16,16-trifluoro-11-(4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(111). Intermediates: I2, P37, and S3. MS (ESI) m/z 1100.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.50 (d, J=2.9 Hz, 1H), 7.88 (dd, J=8.7,4.2 Hz, 3H), 7.72-7.63 (m, 3H), 7.49 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.8Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.8 Hz, 1H), 4.96 (t, J=7.6Hz, 2H), 4.84-4.80 (m, 3H), 4.54 (s, 1H), 4.42-4.32 (m, 4H), 4.25 (d,J=6.6 Hz, 1H), 4.15 (d, J=4.7 Hz, 3H), 4.05-4.00 (m, 1H), 3.92 (d,J=13.3 Hz, 1H), 3.75 (d, J=8.3 Hz, 1H), 3.68 (s, 3H), 3.58 (s, 3H), 3.39(d, J=13.8 Hz, 3H), 2.93-2.71 (m, 5H), 2.28-2.19 (m, 2H), 2.07 (d, J=8.6Hz, 2H), 1.11 (d, J=8.0 Hz, 7H), 1.02 (s, 3H), 0.83 (s, 3H).

Example 112

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(112). Intermediates: I2, P4, and S48. MS (ESI) m/z 1129.9 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.33-8.29 (m, 1H), 8.14 (d, J=9.4 Hz, 1H),8.10 (d, J=2.7 Hz, 1H), 7.74-7.61 (m, 2H), 7.53 (s, 1H), 7.45 (t, J=6.9Hz, 2H), 7.39-7.31 (m, 3H), 7.22 (d, J=8.2 Hz, 3H), 7.09 (d, J=9.9 Hz,1H), 6.98-6.91 (m, 2H), 4.94-4.88 (m, 3H), 4.42 (td, J=7.9, 7.2, 4.1 Hz,2H), 4.35-4.27 (m, 2H), 4.20-4.11 (m, 3H), 3.95 (d, J=13.2 Hz, 3H),3.79-3.65 (m, 11H), 2.94-2.84 (m, 3H), 2.83-2.74 (m, 1H), 1.21-1.10 (m,9H), 1.04 (d, J=7.2 Hz, 3H).

Example 113

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(113). Intermediates: I2, P9, and S48. MS (ESI) m/z 1093.9 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.38 (s, 1H), 8.31-8.28 (m, 1H), 8.06 (s,1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.57-7.52 (m, 3H), 7.48 (s, 1H), 7.41(d, J=8.0 Hz, 2H), 7.32 (d, J=7.4 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 6.95(d, J=8.9 Hz, 1H), 4.94-4.89 (m, 3H), 4.85-4.80 (m, 2H), 4.45-4.37 (m,3H), 4.25 (s, 1H), 4.15 (s, 1H), 4.01-3.84 (m, 6H), 3.74 (d, J=8.9 Hz,1H), 3.68 (s, 3H), 3.60 (s, 3H), 2.89 (d, J=8.9 Hz, 2H), 2.85-2.67 (m,3H), 1.28 (d, J=13.9 Hz, 5H), 1.11 (d, J=12.5 Hz, 6H), 1.01 (s, 3H),0.88-0.81 (m, 3H).

Example 114

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(114). Intermediates: I2, P7, and S57. MS (ESI) m/z 1144.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.52 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.12(s, 2H), 7.71-7.64 (m, 1H), 7.36-7.30 (m, 2H), 7.23 (dd, J=11.8, 8.2 Hz,4H), 7.13 (d, J=9.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 6.78 (d, J=9.9 Hz,1H), 4.46-4.41 (m, 1H), 4.31 (d, J=9.5 Hz, 1H), 4.21-4.00 (m, 7H),3.97-3.85 (m, 3H), 3.78-3.65 (m, 9H), 3.42 (s, 5H), 2.94-2.74 (m, 5H),2.43 (dtd, J=12.8, 8.2, 4.3 Hz, 2H), 2.24 (ddd, J=13.7, 9.2, 5.0 Hz,1H), 1.20-1.10 (m, 9H), 1.03 (s, 3H).

Example 115

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(115). Intermediates: I2, P7, and S50. MS (ESI) m/z 1158.0 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.52 (d, J=0.8 Hz, 1H), 8.30 (dd, J=2.3,0.8 Hz, 1H), 8.12 (d, J=6.0 Hz, 2H), 7.70 (dd, J=8.9, 2.3 Hz, 1H),7.36-7.31 (m, 3H), 7.27-7.20 (m, 5H), 6.96-6.91 (m, 1H), 4.43 (d, J=9.7Hz, 2H), 4.31 (d, J=9.9 Hz, 1H), 4.11 (dq, J=11.3, 6.3, 4.7 Hz, 5H),3.93 (d, J=13.2 Hz, 2H), 3.68 (d, J=10.2 Hz, 9H), 3.56-3.40 (m, 5H),2.93-2.73 (m, 5H), 2.14-2.06 (m, 3H), 1.77 (qd, J=12.1, 4.7 Hz, 3H),1.18-1.11 (m, 10H), 1.03 (s, 3H).

Example 116

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(116). Intermediates: I2, P7, and S48. MS (ESI) m/z 1130.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.53 (d, J=0.7 Hz, 1H), 8.31-8.28 (m, 1H),8.13 (d, J=10.9 Hz, 2H), 7.70 (dd, J=8.9, 2.3 Hz, 1H), 7.36-7.30 (m,3H), 7.23 (dd, J=11.5, 8.1 Hz, 5H), 7.13 (d, J=10.0 Hz, 1H), 6.95 (d,J=8.8 Hz, 1H), 4.90 (t, J=7.7 Hz, 3H), 4.82 (s, 2H), 4.42 (ddd, J=9.9,7.1, 3.6 Hz, 2H), 4.31 (d, J=10.0 Hz, 1H), 4.20-4.09 (m, 3H), 3.93 (d,J=11.8 Hz, 5H), 3.68 (d, J=10.1 Hz, 8H), 2.95-2.73 (m, 5H), 1.21-1.10(m, 10H), 1.03 (s, 4H).

Example 117

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(117). Intermediates: I3, P46, and S3. MS (ESI) m/z 1056.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 7.99 (s, 1H), 7.77 (s, 1H), 7.70 (dd,J=8.9, 2.3 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.39-7.30 (m, 5H), 7.20 (d,J=8.1 Hz, 2H), 6.86 (d, J=8.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.82 (dd,J=8.2, 5.1 Hz, 3H), 4.54 (s, 1H), 4.41-4.31 (m, 4H), 4.18-4.09 (m, 3H),3.97-3.87 (m, 2H), 3.77 (d, J=9.6 Hz, 1H), 3.73-3.60 (m, 9H), 3.44-3.36(m, 2H), 2.96-2.75 (m, 4H), 2.26-2.19 (m, 2H), 2.10-2.04 (m, 2H),1.15-0.97 (m, 11H), 0.77 (s, 9H).

Example 118

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(118). Intermediates: I2, P5, and S7. MS (ESI) m/z 1138.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.52 (d, J=1.0 Hz, 2H), 8.10 (d, J=9.4 Hz, 1H),7.76 (d, J=1.7 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.45 (t, J=58.0 Hz, 1H),7.34 (d, J=7.9 Hz, 2H), 7.26-7.18 (m, 4H), 7.16 (d, J=9.8 Hz, 1H), 6.79(d, J=9.9 Hz, 1H), 6.56 (d, J=1.7 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.76(s, 1H), 4.48-4.36 (m, 1H), 4.28-4.18 (m, 2H), 4.14 (s, 3H), 4.08 (s,1H), 3.98 (d, J=13.7 Hz, 1H), 3.75 (s, 1H), 3.58 (s, 3H), 3.47 (d,J=14.5 Hz, 2H), 2.91 (d, J=9.2 Hz, 2H), 2.83 (d, J=6.6 Hz, 2H),2.27-2.15 (m, 2H), 1.99 (d, J=8.8 Hz, 2H), 1.14 (s, 3H), 1.13 (s, 3H),1.09 (s, 3H), 0.95 (s, 3H).

Example 119

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(119). Intermediates: 12, P47, and S7. MS (ESI) m/z 1133.32 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.97 (s, 1H), 8.52 (s, 1H), 8.14 (d, J=9.4Hz, 1H), 7.34 (dd, J=8.0, 5.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.16 (d,J=10.0 Hz, 2H), 6.79 (d, J=9.9 Hz, 2H), 4.96 (t, J=7.6 Hz, 2H),4.81-4.73 (m, 6H), 4.44 (d, J=9.9 Hz, 2H), 4.29 (d, J=10.0 Hz, 2H), 4.16(d, J=14.0 Hz, 2H), 3.96 (d, J=13.2 Hz, 1H), 3.67 (d, J=15.8 Hz, 10H),3.46 (d, J=14.5 Hz, 1H), 3.20-3.12 (m, 2H), 2.95-2.79 (m, 2H), 2.74 (s,3H), 2.22 (dd, J=14.5, 8.2 Hz, 1H), 1.99 (d, J=8.8 Hz, 1H), 1.27-1.09(m, 10H), 1.04 (s, 6H).

Example 120

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(120). Intermediates: I2, P20, and S7. MS (ESI) m/z 1284.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.73 (s, 2H), 8.53 (s, 2H), 8.19 (d, J=9.4Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.23 (d, J=8.5 Hz, 5H), 6.84 (d, J=9.8Hz, 1H), 5.04-4.92 (m, 5H), 4.80 (d, J=4.3 Hz, 2H), 4.44 (d, J=9.9 Hz,1H), 4.31 (d, J=10.0 Hz, 1H), 4.15 (s, 6H), 3.95 (d, J=13.2 Hz, 1H),3.74 (s, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.47 (dd, J=14.4, 9.6 Hz, 5H),2.91 (d, J=7.7 Hz, 2H), 2.79 (d, J=9.6 Hz, 1H), 2.21 (s, 4H), 1.99 (t,J=7.3 Hz, 5H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 121

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(121). Intermediates: I1, P4, and S7. MS (ESI) m/z 1048.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.44 (s, 2H), 8.01 (d, J=2.7 Hz, 1H), 7.77 (d,J=9.5 Hz, 1H), 7.44 (t, J=59.7 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.26 (d,J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H), 4.87 (dd,J=8.1, 7.0 Hz, 2H), 4.71 (dd, J=8.1, 5.1 Hz, 2H), 4.02 (d, J=13.8 Hz,4H), 3.87 (d, J=13.4 Hz, 1H), 3.80 (s, 1H), 3.72-3.62 (m, 1H), 3.58 (s,3H), 3.55 (s, 2H), 3.38 (d, J=1.6 Hz, 1H), 3.34 (s, 1H), 2.83 (t, J=7.0Hz, 1H), 2.72 (s, 2H), 2.11 (s, 2H), 1.89 (d, J=9.1 Hz, 2H), 0.79 (s,8H), 0.74 (s, 8H).

Example 122

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(122). Intermediates: I2, P6, and S7. MS (ESI) m/z 1121.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.52 (s, 2H), 8.09 (d, J=9.4 Hz, 1H), 8.04 (d,J=2.7 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.49 (t, J=60.0 Hz, 1H), 7.44 (d,J=8.1 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.09 (d,J=9.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.76 (d, J=9.9 Hz, 1H), 4.95 (t,J=7.6 Hz, 2H), 4.82-4.78 (m, 2H), 4.75 (s, 1H), 4.39 (d, J=9.8 Hz, 1H),4.24 (d, J=9.8 Hz, 1H), 4.18 (d, J=8.3 Hz, 1H), 4.16-4.08 (m, 2H), 4.00(d, J=13.1 Hz, 1H), 3.88 (d, J=13.4 Hz, 1H), 3.74 (s, 1H), 3.67 (s, 3H),3.59 (s, 3H), 3.46 (d, J=14.5 Hz, 2H), 2.96-2.86 (m, 2H), 2.86-2.68 (m,2H), 2.29-2.13 (m, 2H), 2.04-1.88 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H),1.02 (s, 3H), 0.84 (s, 3H).

Example 123

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(123). Intermediates: I2, P4, and S58a. MS (ESI) m/z 1088.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 2H), 7.53 (t, J=59.7 Hz, 1H), 7.45(d, J=8.2 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 7.14(d, J=10.1 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 6.82 (d, J=10.0 Hz, 1H),4.50-4.39 (m, 1H), 4.38 (s, 2H), 4.34-4.26 (m, 1H), 4.14 (d, J=12.5 Hz,2H), 4.10-3.99 (m, 2H), 3.94 (d, J=13.1 Hz, 1H), 3.80-3.72 (m, 2H), 3.69(s, 3H), 3.66 (s, 3H), 3.45-3.38 (m, 2H), 2.94-2.82 (m, 3H), 2.82-2.73(m, 1H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.06-0.99 (m, 3H).

Example 124

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8-(4((6-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(124). Intermediates: I2, P4, and S59. MS (ESI) m/z 1157.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.28 (d, J=2.2 Hz, 1H), 8.20-8.07 (m, 1H),7.74-7.66 (m, 1H), 7.48-7.30 (m, 4H), 7.22 (d, J=8.0 Hz, 2H), 6.93 (d,J=2.8 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 4.44 (s, 1H), 4.31 (s, 1H), 4.28(s, 3H), 4.14 (d, J=12.1 Hz, 2H), 3.94 (d, J=13.1 Hz, 1H), 3.83-3.77 (m,2H), 3.68 (d, J=12.0 Hz, 7H), 3.44 (s, 4H), 3.35 (s, 3H), 2.94-2.84 (m,3H), 2.78 (dd, J=12.6, 9.1 Hz, 1H), 2.32-2.24 (m, 2H), 2.06 (d, J=8.6Hz, 2H), 1.24-1.09 (m, 8H), 1.03 (s, 2H).

Example 125

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(125). Intermediates: I2, P39, and S3. MS (ESI) m/z 1128.8 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.56 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.14(d, J=9.5 Hz, 1H), 8.01-7.88 (m, 2H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.56(d, J=8.4 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.83(dd, J=28.9, 9.4 Hz, 2H), 4.96 (t, J=7.6 Hz, 2H), 4.48-4.40 (m, 1H),4.39-4.27 (m, 3H), 4.22-4.12 (m, 4H), 3.98 (d, J=13.1 Hz, 1H), 3.75 (s,1H), 3.70 (s, 3H), 3.64 (s, 3H), 3.46-3.37 (m, 2H), 2.95-2.75 (m, 5H),2.46 (s, 3H), 2.24 (dd, J=9.9, 4.5 Hz, 2H), 2.07 (d, J=8.6 Hz, 2H),1.34-1.21 (m, 1H), 1.19-1.06 (m, 9H), 1.03 (s, 3H).

Example 126

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(126) Intermediates: I2, P42, and S3. MS (ESI) m/z 1105.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.15 (d, J=9.4 Hz, 1H), 7.70 (dd, J=9.4, 2.8Hz, 2H), 7.35 (dd, J=14.0, 8.3 Hz, 4H), 7.22 (d, J=7.9 Hz, 2H), 6.86 (d,J=8.9 Hz, 1H), 6.81-6.72 (m, 2H), 4.97 (t, J=7.6 Hz, 2H), 4.53 (s, 1H),4.44 (d, J=9.5 Hz, 1H), 4.34 (t, J=12.5 Hz, 3H), 4.15 (s, 3H), 3.95 (d,J=13.2 Hz, 1H), 3.68 (d, J=14.3 Hz, 10H), 3.39 (d, J=13.9 Hz, 2H),2.94-2.76 (m, 4H), 2.27-2.19 (m, 2H), 2.08 (d, J=8.5 Hz, 2H), 1.20-1.10(m, 9H), 1.03 (s, 3H).

Example 127

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(127). Intermediates: I2, P43, and S3. MS (ESI) m/z 1188.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.65 (d, J=6.6 Hz, 1H), 8.32-8.26 (m, 1H),7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.62-7.52 (m, 2H), 7.34 (d, J=7.9 Hz, 2H),7.30-7.19 (m, 3H), 6.84 (dd, J=21.8, 9.4 Hz, 1H), 5.76-5.64 (m, 1H),5.11 (t, J=6.9 Hz, 2H), 4.95 (t, J=7.6 Hz, 2H), 4.90-4.73 (m, 3H),4.59-4.51 (m, 1H), 4.44 (t, J=5.1 Hz, 1H), 4.32 (td, J=14.6, 5.4 Hz,3H), 4.25-4.12 (m, 4H), 4.05-3.95 (m, 1H), 3.68 (d, J=17.7 Hz, 5H),3.48-3.39 (m, 2H), 3.35 (s, 4H), 2.91 (d, J=8.2 Hz, 2H), 2.83 (s, 1H),2.24 (dd, J=9.7, 4.5 Hz, 2H), 2.07 (d, J=8.6 Hz, 2H), 1.15 (d, J=5.7 Hz,8H), 1.04 (s, 2H).

Example 128

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(128). Intermediates: I2, P41, and S3. MS (ESI) m/z 1119.9 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.29 (d, J=2.2 Hz, 1H), 7.77-7.67 (m, 1H),7.61 (d, J=2.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 4H), 7.22 (d, J=8.2 Hz, 2H),6.88 (d, J=8.9 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 4.95 (t, J=7.6 Hz, 2H),4.85 (dd, J=8.2, 5.1 Hz, 2H), 4.55 (p, J=6.2 Hz, 1H), 4.45 (d, J=8.5 Hz,1H), 4.34 (dd, J=14.5, 2.5 Hz, 3H), 4.19-4.08 (m, 4H), 3.93 (s, 4H),3.68 (d, J=9.4 Hz, 6H), 3.48-3.39 (m, 2H), 3.35 (s, 1H), 2.99 (s, 1H),2.94-2.73 (m, 5H), 2.27-2.19 (m, 2H), 2.08 (t, J=6.9 Hz, 2H), 1.35-1.26(m, 1H), 1.24-1.09 (m, 9H), 1.03 (s, 3H).

Example 129

Methyl((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(129). Intermediates: I2, P40, and S3. MS (ESI) m/z 1147.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.33-8.26 (m, 1H), 8.16 (d, J=9.4 Hz, 1H),7.70 (dt, J=9.1, 2.4 Hz, 1H), 7.54 (d, J=7.3 Hz, 2H), 7.37-7.32 (m, 2H),7.23 (d, J=8.2 Hz, 2H), 6.91-6.77 (m, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.84(dd, J=8.2, 5.1 Hz, 2H), 4.59-4.52 (m, 1H), 4.52-4.40 (m, 1H), 4.39-4.24(m, 3H), 4.22-4.13 (m, 4H), 3.96 (d, J=12.9 Hz, 1H), 3.75 (d, J=9.0 Hz,1H), 3.72-3.63 (m, 6H), 3.46-3.38 (m, 2H), 2.91 (d, J=8.7 Hz, 2H),2.88-2.74 (m, 2H), 2.36-2.20 (m, 3H), 2.08 (d, J=8.6 Hz, 2H), 1.32-1.16(m, 6H), 1.15 (s, 4H), 1.13 (s, 3H), 1.03 (s, 2H), 0.89 (s, 1H).

Example 130

Methyl((4S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(130). Intermediates: I2, P28, and S3. MS (ESI) m/z 1116.6 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.71 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.17(d, J=8.5 Hz, 1H), 8.09 (t, J=7.8 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.70(dd, J=8.8, 2.3 Hz, 1H), 7.64-7.52 (m, 3H), 7.34 (d, J=7.8 Hz, 2H), 7.23(d, J=8.0 Hz, 2H), 7.14 (d, J=9.5 Hz, 1H), 6.84 (dd, J=25.9, 9.4 Hz,2H), 4.96 (t, J=7.6 Hz, 2H), 4.83 (dd, J=8.2, 5.1 Hz, 2H), 4.55 (d,J=7.8 Hz, 1H), 4.48-4.41 (m, 1H), 4.35 (dd, J=14.5, 2.5 Hz, 3H),4.19-4.13 (m, 4H), 3.99 (d, J=7.6 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 4H),3.64 (s, 3H), 3.46-3.32 (m, 3H), 2.93 (s, 2H), 2.24 (dd, J=9.6, 4.6 Hz,2H), 2.07 (d, J=8.6 Hz, 2H), 1.19-1.10 (m, 9H), 1.03 (s, 3H).

Example 131

Methyl((5S,10S,11S,14S)-8-(4-ethynyl-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(131a). The title compound 131a was prepared according to the methodpresented for the synthesis of compound 1a but instead utilizing P38. MS(ESI) m/z 924.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.52 (d, J=8.0Hz, 2H), 7.00 (dd, J=11.2, 7.8 Hz, 4H), 4.44 (s, 1H), 4.27 (s, 1H),4.17-4.01 (m, 2H), 3.90 (d, J=13.2 Hz, 1H), 3.71 (t, J=5.9 Hz, 8H), 2.82(d, J=7.8 Hz, 2H), 2.77-2.67 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11(s, 3H), 1.02 (s, 3H).

Methyl((5S,8S,9S,14S)-11-(4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(131b). To a solution of 131a (62 mg, 0.07 mmol) in THF (2 mL) was addedcopper (52 mg, 0.818 mmol), 10% CuSO₄ (100 uL), and1-azidobicyclo[1.1.1]pentane in CuSO₄ (0.300 ml, 0.082 mmol). After 2h,added more 1-azidobicyclo[1.1.1]pentane in CuSO₄ (0.300 ml, 0.082 mmol).Stirred for another 2h, added more 1-azidobicyclo[1.1.1]pentane in CuSO₄(0.300 ml, 0.082 mmol), then stirred for 48h. The reaction waspartitioned with EtOAc and brine. The organic extract was washed withNH4Cl solution and dried over Na₂SO₄ filtered and concentrated underreduced pressure. The residue was purified by silica chromatography(25%-75% EtOAc/hex to yield 131b. MS (ESI) m/z 1032.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.43 (d,J=8.1 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 4.44 (s, 1H), 4.30 (s, 1H),4.17-4.03 (m, 3H), 3.93 (d, J=13.2 Hz, 1H), 3.71 (s, 4H), 3.66 (s, 3H),2.86-2.67 (m, 5H), 2.45 (s, 7H), 1.16 (s, 4H), 1.14 (s, 3H), 1.11 (s,3H), 1.02 (s, 3H), 0.89 (d, J=6.7 Hz, 1H).

Methyl((5S,8S,9S,14S)-11-(4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(131) The title compound 131 was prepared according to the methodpresented for the synthesis of compound 1 but instead utilizing 131b andS7. MS (ESI) m/z 1174.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.53 (s,3H), 8.51 (s, 1H), 8.19 (d, J=9.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 3H), 7.34(d, J=7.8 Hz, 3H), 7.23 (d, J=7.8 Hz, 3H), 7.18 (d, J=9.9 Hz, 1H), 6.83(d, J=10.1 Hz, 1H), 4.96 (t, J=7.6 Hz, 3H), 4.80 (d, J=7.3 Hz, 6H), 4.44(d, J=9.6 Hz, 1H), 4.30 (d, J=9.9 Hz, 1H), 4.15 (d, J=6.5 Hz, 5H), 3.94(d, J=13.1 Hz, 1H), 3.72 (s, 2H), 3.68 (d, J=9.6 Hz, 8H), 3.48 (s, 2H),3.44 (s, 1H), 2.96-2.81 (m, 3H), 2.79 (d, J=10.1 Hz, 1H), 2.74 (s, 1H),2.45 (s, 8H), 2.21 (d, J=10.4 Hz, 3H), 1.99 (d, J=9.2 Hz, 3H), 1.16 (s,5H), 1.14 (s, 8H), 1.11 (s, 4H), 1.02 (s, 4H).

Example 132

Synthesis of tert-butyl2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate(132a). The title compound 132a was prepared according to the methodpresented for the synthesis of compound 1a but instead utilizing I2a andP7. MS (ESI) m/z 764.0 [M+H]⁺.

Synthesis of tert-butyl2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-4-(4-((6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)ethynyl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate(132b). The title compound 132b was prepared according to the methodpresented for the synthesis of compound 1 but instead utilizing 132a andS23. MS (ESI) m/z 852.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.53 (s,1H), 8.19-8.08 (m, 2H), 7.93 (d, J=9.4 Hz, 1H), 7.50 (t, J=59.7 Hz, 1H),7.40 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.1 Hz, 5H), 4.07 (d, J=12.9 Hz, 2H),3.74 (ddd, J=10.7, 6.3, 2.5 Hz, 1H), 3.62 (s, 1H), 2.87-2.69 (m, 3H),1.37 (s, 7H), 1.31 (s, 5H), 1.27 (s, 3H), 1.25 (s, 3H).

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(132) The title compound 132 was prepared according to the methodpresented for the synthesis of intermediate I2 but instead utilizing132b. MS (ESI) m/z 1102.3 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.54(d, J=0.7 Hz, 1H), 8.25-8.10 (m, 3H), 7.83 (d, J=9.1 Hz, 1H), 7.51 (s,1H), 7.35 (d, J=7.3 Hz, 2H), 7.24 (t, J=7.7 Hz, 4H), 7.15 (dd, J=20.4,9.7 Hz, 1H), 6.82 (d, J=10.0 Hz, 1H), 4.44 (d, J=9.8 Hz, 1H), 4.31 (d,J=9.9 Hz, 1H), 4.21-4.03 (m, 4H), 3.93 (d, J=13.2 Hz, 1H), 3.81-3.61 (m,6H), 2.97-2.80 (m, 2H), 2.80-2.66 (m, 2H), 2.03 (s, 1H), 1.25 (d, J=6.2Hz, 6H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 133

Synthesis of tert-butyl2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate(133a) A mixture of I2a (0.28 g, 0.53 mmol) and P1 (172 mg, 0.67 mmol)were dissolved in a mixture of THF/AcOH (12 mL, 3:1) After stirring atroom temperature for 15 min sodium cyanoborohydride (2.49 mmol/gr onresin, 0.44 g, 1.09 mmol) was added. The reaction mixture was stirredovernight, then filtered and the filtered resin was rinsed several timeswith EtOAc. The combined filtrate was concentrated under reducedpressure; the residue was recrystallized/precipitated from EtOAc/hexanesto afford 133a (351.6 mg, 87.3%). MS (ESI) m/z 764.09 [M+H]^(|).

Synthesis of methyl((5S,10S,11S,14S)-8-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(133b). 133a (75%, 0.3 g, 0.29 mmol) was dissolved in DCM (10 mL) andHCl (4.0M in dioxane, 2.6 mL). The reaction was stirred for 3h thenconcentrated under reduce pressure the crude material was dissolved inDCM (10 mL) and HATU (0.24 g, 0.64 mmol), N,N-diisopropylethylamine (0.6ml, 0 mol) was added followed by A3 (0.21 g, 0.86 mmol). The reactionwas stirred at stirred at room temperature overnight. The reactionmixture was diluted with 5 mL of MeOH and concentrated. The cruderesidue was diluted with EtOAc and washed with 5% LiCl, saturatedNaHCO3, and brine then dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (30% to 70% EtOAc/Hex) to afford 133b (296 mg, 67%). MS(ESI) m/z 1014.6 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J=1.2Hz, 1H), 8.01 (d, J=1.3 Hz, 1H), 7.58 (t, J=59.9 Hz, 1H), 7.52 (d, J=7.9Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 4.45 (s, 1H),4.30 (s, 1H), 4.14 (s, 0H), 3.93 (d, J=13.2 Hz, 1H), 3.71 (s, 3H), 3.66(s, 3H), 2.92-2.67 (m, 4H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H),1.02 (s, 3H).

Methyl((5S,10S,11S,14S)-8-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(133) In a vial, a solution of 133b (50 mg, 0.05 mmol), S7 (17 mg, 0.06mmol), copper (I) iodide (4.0 mg, 0.02 mmol),trans-Dichlorobis(triphenylphosphine)palladium (II) (99%, 11.1 mg, 0.02mmol) in a mixture of and MeCN: Et₃N 3:1(1mL) was degassed and thenstirred at room temperature overnight. Concentrated under reducedpressure. Purification by HPLC and Lyophilized to give 133. MS (ESI) m/z1156.4 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 2H), 8.09 (d,J=17.5 Hz, 2H), 7.93 (s, 1H), 7.49 (t, J=60.0 Hz, 1H), 7.27 (dd, J=18.4,8.1 Hz, 3H), 7.14 (d, J=8.0 Hz, 2H), 6.73 (d, J=9.9 Hz, 1H), 4.86 (d,J=7.6 Hz, 2H), 4.72 (dd, J=8.2, 5.0 Hz, 2H), 4.35 (d, J=8.7 Hz, 1H),4.22 (d, J=9.8 Hz, 1H), 4.03 (d, J=12.8 Hz, 4H), 3.84 (d, J=13.2 Hz,1H), 3.58 (d, J=8.6 Hz, 5H), 3.37 (d, J=14.4 Hz, 2H), 2.90-2.62 (m, 4H),2.56 (s, 1H), 2.12 (d, J=11.1 Hz, 2H), 1.90 (d, J=9.0 Hz, 2H), 1.07 (s,3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H).

Example 134

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamateIntermediates: P4, A3, and S5. MS (ESI) m/z 1137.1 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.11 (d, J=9.4 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H),7.75-7.50 (m, 6H), 7.46 (d, J=16.5 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.28(d, J=9.5 Hz, 3H), 7.15 (d, J=8.0 Hz, 3H), 6.85 (d, J=2.7 Hz, 1H), 6.73(d, J=10.0 Hz, 1H), 4.79-4.71 (m, 5H), 4.35 (d, J=9.9 Hz, 1H), 4.22 (d,J=10.0 Hz, 1H), 4.06 (d, J=13.5 Hz, 3H), 3.85 (d, J=13.0 Hz, 1H), 3.65(s, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 3.08 (s, 4H), 2.83 (d, J=8.0 Hz,2H), 2.73-2.62 (m, 1H), 1.07 (s, 4H), 1.05 (s, 3H), 1.02 (s, 4H), 0.94(s, 3H).

Example 135

Methyl((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(135). Intermediates: P14, A3, and S6. MS (ESI) m/z 1120.2 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.46 (d, J=2.9 Hz, 1H), 8.16 (d, J=2.1 Hz,1H), 8.11 (d, J=9.2 Hz, 1H), 7.87 (dd, J=8.8, 4.3 Hz, 1H), 7.65-7.55 (m,2H), 7.51 (d, J=8.7 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.1 Hz,3H), 6.74 (d, J=10.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 4.95 (s, 1H), 4.86(dd, J=8.4, 6.3 Hz, 1H), 4.61 (s, 1H), 4.49 (dq, J=11.2, 6.0, 5.5 Hz,2H), 4.41 (s, 1H), 4.35 (d, J=9.7 Hz, 1H), 4.21 (d, J=10.0 Hz, 1H), 4.07(d, J=13.3 Hz, 2H), 3.87 (d, J=13.1 Hz, 1H), 3.74-3.62 (m, 2H), 3.60 (s,3H), 3.55 (s, 3H), 2.87-2.73 (m, 3H), 2.73-2.65 (m, 1H), 2.23 (s, 2H),1.06 (d, J=5.4 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 136

methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(136). Intermediates: P13, A3, and S8. MS (ESI) m/z 1118.6 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.22 (d, J=2.3 Hz, 1H), 8.10 (d, J=9.4 Hz,1H), 7.61 (dt, J=5.4, 2.6 Hz, 2H), 7.59-7.50 (m, 1H), 7.47 (dt, J=7.7,4.1 Hz, 1H), 7.30-7.19 (m, 4H), 7.13 (d, J=8.1 Hz, 2H), 7.06 (s, 0H),6.86 (d, J=8.9 Hz, 1H), 6.72 (d, J=9.9 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H),4.53 (dd, J=22.7, 13.2 Hz, 2H), 4.42-4.30 (m, 1H), 4.26-4.18 (m, 1H),4.03 (d, J=13.2 Hz, 4H), 3.84 (d, J=13.1 Hz, 1H), 3.76 (t, J=12.7 Hz,1H), 3.59 (d, J=9.3 Hz, 6H), 3.49 (d, J=11.0 Hz, 1H), 3.44-3.35 (m, 0H),2.81 (d, J=7.3 Hz, 3H), 2.72-2.63 (m, 1H), 1.08 (s, 3H), 1.05 (s, 4H),1.04 (d, J=2.8 Hz, 0H), 1.02 (s, 2H), 1.00-0.95 (m, 1H), 0.94 (s, 3H).

Example 137

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(137). Intermediates: P15, A3, and S8. MS (ESI) m/z 1118.6 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.56 (dd, J=8.6, 5.6 Hz, 1H), 8.21 (d,J=2.2 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.67 (dd, J=10.3, 2.4 Hz, 1H),7.61 (dd, J=8.9, 2.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.24 (d, J=7.9 Hz,2H), 7.16-7.08 (m, 3H), 6.86 (d, J=8.9 Hz, 1H), 6.74 (d, J=10.0 Hz, 1H),4.52 (dd, J=23.4, 12.6 Hz, 2H), 4.35 (d, J=10.0 Hz, 1H), 4.21 (d, J=9.9Hz, 1H), 4.07 (t, J=10.4 Hz, 4H), 3.87 (d, J=13.2 Hz, 1H), 3.75 (t,J=12.6 Hz, 1H), 3.64 (s, 1H), 3.60 (s, 3H), 3.55 (s, 2H), 3.48 (d,J=10.7 Hz, 1H), 3.39 (t, J=10.4 Hz, 1H), 2.88-2.73 (m, 4H), 2.73-2.64(m, 1H), 1.06 (d, J=5.6 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 138

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(138). Intermediates: P15, A3, and S6. MS (ESI) m/z 1120.6 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.56 (dd, J=8.6, 5.6 Hz, 1H), 8.16 (s, 1H),8.11 (d, J=9.5 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.58 (dd, J=14.3, 8.7Hz, 3H), 7.23 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.0 Hz, 4H), 6.74 (d, J=10.2Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 4.95 (s, 1H), 4.61 (s, 1H), 4.49 (dd,J=11.6, 6.4 Hz, 1H), 4.41 (s, 1H), 4.35 (d, J=10.0 Hz, 1H), 4.21 (d,J=9.9 Hz, 1H), 4.08 (d, J=12.8 Hz, 2H), 3.87 (d, J=13.0 Hz, 1H), 3.66(d, J=16.3 Hz, 2H), 3.60 (d, J=1.1 Hz, 3H), 3.55 (s, 3H), 2.81 (d, J=7.8Hz, 2H), 2.71 (d, J=9.5 Hz, 1H), 2.23 (s, 2H), 1.06 (d, J=4.6 Hz, 6H),1.02 (s, 3H), 0.93 (s, 3H).

Example 139

Methyl((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamateate(139). Intermediates: P14, A3, and S4. MS (ESI) m/z 1120.2 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.46 (d, J=2.9 Hz, 1H), 8.24 (d, J=2.3 Hz,1H), 8.10 (d, J=9.3 Hz, 1H), 7.96-7.86 (m, 1H), 7.65 (dd, J=8.8, 2.3 Hz,1H), 7.59 (td, J=8.5, 3.0 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.24 (d,J=7.9 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.08 (d, J=9.9 Hz, 1H), 6.73 (d,J=10.6 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 4.96-4.83 (m, 4H), 4.59-4.47 (m,2H), 4.42-4.31 (m, 1H), 4.31-4.19 (m, 1H), 4.07 (d, J=13.4 Hz, 4H), 3.87(d, J=13.2 Hz, 1H), 3.64 (s, 2H), 3.60 (s, 3H), 3.56 (s, 3H), 2.82 (d,J=8.4 Hz, 2H), 2.74-2.65 (m, 1H), 2.02 (d, J=11.0 Hz, 1H), 1.07 (s, 4H),1.06 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 140

Methyl((5S,10S,11S,14S)-8-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(140). Intermediates: P15, A3, and S4. MS (ESI) m/z 1120.2 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.66 (dd, J=8.6, 5.6 Hz, 1H), 8.33 (s, 1H),8.21 (d, J=9.3 Hz, 1H), 7.76 (t, J=9.9 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H),7.34 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.7 Hz, 3H), 6.84 (d, J=10.1 Hz, 0H),6.78 (d, J=8.9 Hz, 1H), 4.61 (dd, J=8.2, 4.0 Hz, 2H), 4.45 (d, J=10.0Hz, 1H), 4.31 (d, J=10.0 Hz, 1H), 4.18 (d, J=12.4 Hz, 2H), 3.99 (s, 0H),3.74 (s, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 2.91 (d, J=8.1 Hz, 2H), 2.80(d, J=9.8 Hz, 1H), 2.11 (d, J=10.9 Hz, 1H), 1.33-1.23 (m, 1H), 1.16 (s,4H), 1.15 (s, 3H), 1.12 (s, 2H), 1.03 (s, 3H).

Example 141

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(141). Intermediates: P4, A3, and S10. MS (ESI) m/z 1143 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.12 (d, J=2.3 Hz, 1H), 8.08 (d, J=9.4 Hz, 1H),8.01 (d, J=2.7 Hz, 1H), 7.62-7.42 (m, 3H), 7.36 (d, J=8.2 Hz, 2H), 7.22(d, J=7.9 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.06 (d, J=9.9 Hz, 1H), 6.85(d, J=2.8 Hz, 1H), 6.72 (dd, J=9.5, 5.4 Hz, 2H), 4.56 (d, J=5.9 Hz, 2H),4.34 (d, J=9.9 Hz, 1H), 4.27-4.15 (m, 3H), 4.05 (d, J=12.1 Hz, 2H), 3.85(d, J=13.1 Hz, 1H), 3.64 (s, 2H), 3.60 (s, 3H), 3.56 (d, J=8.7 Hz, 7H),2.75 (dd, J=44.1, 8.8 Hz, 4H), 2.46 (t, J=5.0 Hz, 4H), 1.32 (s, 3H),1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

Example 142

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(142). Intermediates: P4, A3, and S11. MS (ESI) m/z 1170.2 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.29 (d, J=2.3 Hz, 1H), 8.17 (d, J=9.4 Hz,1H), 8.10 (d, J=2.7 Hz, 1H), 7.76-7.60 (m, 2H), 7.60-7.52 (m, 1H), 7.45(d, J=8.2 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.13(d, J=9.8 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 6.79(d, J=10.0 Hz, 1H), 4.45 (s, 0H), 4.42-4.27 (m, 2H), 4.23 (s, 1H),4.20-4.05 (m, 2H), 4.05-3.89 (m, 3H), 3.88-3.56 (m, 8H), 3.06-2.85 (m,3H), 2.85-2.69 (m, 1H), 2.50 (d, J=12.5 Hz, 1H), 2.32 (s, 2H), 2.22-2.00(m, 3H), 1.16 (s, 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 143

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(143). Intermediates: P4, A3, and S12. MS (ESI) m/z 1170.1 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.29 (d, J=2.2 Hz, 1H), 8.17 (d, J=9.3 Hz,1H), 8.10 (d, J=2.7 Hz, 1H), 7.74-7.60 (m, 2H), 7.59-7.50 (m, 1H), 7.45(d, J=8.2 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.13(d, J=9.7 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 6.79(d, J=9.9 Hz, 1H), 4.44 (d, J=10.1 Hz, 1H), 4.30 (d, J=9.9 Hz, 1H), 4.23(s, 1H), 4.14 (d, J=12.3 Hz, 2H), 3.97 (t, J=14.4 Hz, 1H), 3.86-3.57 (m,8H), 2.97-2.84 (m, 3H), 2.84-2.68 (m, 1H), 2.49 (s, 1H), 2.32 (s, 2H),2.22-2.04 (m, 3H), 1.16 (s, 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s,3H).

Example 144

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(144). Intermediates: P4, A3, and S13. MS (ESI) m/z 1170.9 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.23-8.13 (m, 1H), 8.10 (d, J=2.8 Hz, 1H),7.57 (dd, J=8.9, 2.4 Hz, 1H), 7.53 (t, J=59.8 Hz, 1H), 7.45 (d, J=8.2Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 6.94 (d, J=2.7Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 4.43 (s, 1H), 4.30 (s, 1H), 4.14 (d,J=12.1 Hz, 2H), 3.95 (d, J=13.2 Hz, 1H), 3.84 (dt, J=8.2, 4.5 Hz, 2H),3.69 (s, 3H), 3.66 (s, 3H), 3.49 (d, J=7.1 Hz, 1H), 3.39 (s, 1H), 3.11(dt, J=11.9, 2.1 Hz, 2H), 2.90 (d, J=8.0 Hz, 2H), 2.83-2.76 (m, 1H),2.73 (d, J=5.0 Hz, 1H), 2.69 (s, 0H), 2.62 (d, J=4.9 Hz, 1H), 2.46 (d,J=13.4 Hz, 1H), 1.97 (s, 2H), 1.67 (d, J=9.0 Hz, 2H), 1.43 (s, 3H), 1.16(s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 145

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-((S)-tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(145). Intermediates: P4, A3, and S15. MS (ESI) m/z 1143.5 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.36-8.26 (m, 1H), 8.19 (d, J=9.2 Hz, 1H),8.11 (d, J=2.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H),7.67-7.61 (m, 0H), 7.57 (dd, J=7.3, 3.3 Hz, 1H), 7.54 (s, 1H), 7.45 (d,J=8.2 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.15 (s,1H), 6.99-6.86 (m, 2H), 6.81 (d, J=10.1 Hz, 1H), 4.45 (s, 0H), 4.31 (d,J=10.0 Hz, 1H), 4.26-4.02 (m, 5H), 4.00-3.82 (m, 3H), 3.75 (d, J=8.4 Hz,1H), 3.68 (d, J=10.9 Hz, 6H), 2.97-2.85 (m, 3H), 2.55-2.35 (m, 1H),2.28-2.16 (m, 1H), 1.16 (s, 4H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s,3H).

Example 146

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-((R)-tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(146). Intermediates: P4, A3, and S14. MS (ESI) m/z 1143.5 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.30 (d, J=2.3 Hz, 1H), 8.19 (d, J=9.1 Hz,1H), 8.11 (d, J=2.8 Hz, 1H), 7.71 (d, J=2.4 Hz, 0H), 7.69 (s, 1H),7.68-7.61 (m, 1H), 7.60-7.55 (m, 1H), 7.54 (s, 1H), 7.45 (d, J=8.2 Hz,2H), 7.33 (d, J=7.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 3H), 6.96-6.85 (m, 2H),6.81 (d, J=9.9 Hz, 1H), 4.44 (d, J=9.8 Hz, 1H), 4.31 (d, J=10.0 Hz, 1H),4.23-4.07 (m, 4H), 3.95 (d, J=13.3 Hz, 1H), 3.92-3.86 (m, 1H), 3.75 (d,J=8.2 Hz, 2H), 3.69 (s, 4H), 3.66 (s, 3H), 3.00-2.82 (m, 3H), 2.79 (d,J=10.0 Hz, 1H), 2.42 (s, 0H), 2.21 (d, J=8.5 Hz, 0H), 1.16 (s, 5H), 1.15(s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).

Example 147

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(147). Intermediates: P22, A3, and S3. MS (ESI) m/z 1282.4 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.43-8.31 (m, 1H), 8.20 (d, J=2.3 Hz, 1H),7.84 (d, J=9.0 Hz, 1H), 7.60 (dd, J=8.8, 2.3 Hz, 1H), 7.24 (d, J=7.9 Hz,2H), 7.17-7.04 (m, 4H), 6.86 (d, J=9.0 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H),6.71 (d, J=10.0 Hz, 1H), 4.87 (t, J=7.7 Hz, 4H), 4.74-4.68 (m, 4H),4.37-4.17 (m, 6H), 4.10-3.99 (m, 6H), 3.86 (d, J=13.1 Hz, 1H), 3.67-3.62(m, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 3.34-3.25 (m, 5H), 2.81 (d, J=7.7Hz, 2H), 2.74-2.65 (m, 1H), 2.19-2.10 (m, 4H), 2.03-1.93 (m, 4H), 1.07(s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 148

Methyl((5S,8S,9S,14S)-11-(2-chloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(148). Intermediates: P25, A3, and S3. MS (ESI) m/z 1114.7 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.55 (d, J=5.0 Hz, 1H), 8.20 (d, J=2.1 Hz,1H), 8.04 (d, J=9.5 Hz, 1H), 7.94-7.85 (m, 1H), 7.82 (d, J=8.1 Hz, 1H),7.77-7.70 (m, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.8, 2.3 Hz, 1H),7.42-7.32 (m, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 6.77(d, J=8.8 Hz, 1H), 6.71 (d, J=10.3 Hz, 1H), 4.87 (t, J=7.6 Hz, 2H),4.73-4.66 (m, 2H), 4.31 (d, J=10.0 Hz, 1H), 4.18 (d, J=9.7 Hz, 1H),4.14-4.03 (m, 3H), 3.99 (d, J=14.2 Hz, 1H), 3.74-3.66 (m, 1H), 3.58 (s,3H), 3.48 (s, 3H), 3.29 (s, 1H), 2.87-2.68 (m, 2H), 2.21-2.07 (m, 1H),2.03-1.93 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H), 0.84 (s,3H).

Example 149

Methyl((5S,8S,9S,14S)-11-(2,6-dichloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(149). Intermediates: P24, A3, and S3. MS (ESI) m/z 1148.5 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.56 (d, J=5.0 Hz, 1H), 8.20 (d, J=2.2 Hz,1H), 8.04 (d, J=9.4 Hz, 1H), 7.88 (s, 2H), 7.83 (d, J=7.8 Hz, 2H),7.64-7.54 (m, 1H), 7.33 (t, J=5.7 Hz, 1H), 7.23 (d, J=7.7 Hz, 2H), 7.12(d, J=8.0 Hz, 2H), 6.77 (d, J=8.9 Hz, 1H), 6.71 (d, J=10.1 Hz, 1H), 4.87(t, J=7.5 Hz, 2H), 4.71 (dd, J=8.2, 4.9 Hz, 2H), 4.36-4.23 (m, 2H), 4.20(d, J=9.9 Hz, 1H), 4.12-3.98 (m, 4H), 3.69-3.62 (m, 1H), 3.59 (s, 3H),3.54 (s, 3H), 3.29 (s, 1H), 2.83-2.75 (m, 2H), 2.72-2.62 (m, 1H),2.17-2.08 (m, 1H), 2.03-1.93 (m, 2H), 1.05 (s, 6H), 0.99 (s, 3H), 0.89(s, 3H).

Example 150

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(150). Intermediates: P4, A3, and S44. MS (ESI) m/z 1171.1 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.17 (d, J=2.2 Hz, 1H), 8.07 (d, J=9.4 Hz,1H), 8.01 (d, J=2.7 Hz, 1H), 7.61-7.55 (m, 3H), 7.44 (s, 1H), 7.35 (d,J=8.3 Hz, 2H), 7.30-7.22 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.02 (d, J=9.9Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.69 (d, J=9.9 Hz, 1H), 4.88-4.80 (m,2H), 4.73-4.68 (m, 2H), 4.41 (s, 1H), 4.34 (d, J=9.9 Hz, 1H), 4.21 (d,J=10.0 Hz, 1H), 4.10-3.98 (m, 4H), 3.85 (d, J=13.2 Hz, 1H), 3.64 (s,1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.48 (d, J=13.5 Hz, 2H), 3.38 (d, J=1.7Hz, 1H), 3.35 (s, 1H), 3.25 (s, 1H), 2.85-2.74 (m, 3H), 2.72-2.65 (m,1H), 2.27 (s, 5H), 2.17-2.11 (m, 2H), 1.06 (d, J=6.7 Hz, 6H), 1.02 (s,3H), 0.93 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71,-77.88, -96.97 (dd, J=59.8, 18.8 Hz), -114.92.

Example 151

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(151). Intermediates: P4, A3, and S46. MS (ESI) m/z 1171.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.17 (d, J=9.3 Hz, 1H), 8.10(d, J=2.7 Hz, 1H), 7.68 (s, 0H), 7.53 (s, 1H), 7.45 (d, J=8.2 Hz, 2H),7.38 (s, 0H), 7.34 (d, J=7.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 7.11 (d,J=9.8 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 6.82 (s, 0H), 6.79 (s, 1H),4.99-4.89 (m, 2H), 4.83-4.77 (m, 2H), 4.51 (s, 1H), 4.47-4.42 (m, 1H),4.35 (s, 1H), 4.31 (s, 1H), 4.29 (s, 0H), 4.16 (s, 1H), 4.13 (s, 3H),3.95 (d, J=13.2 Hz, 1H), 3.74 (s, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38(s, 1H), 3.34 (s, 3H), 2.94-2.84 (m, 3H), 2.78 (dd, J=12.5, 9.0 Hz, 1H),2.44 (s, 3H), 2.25-2.18 (m, 2H), 2.10-2.04 (m, 2H), 1.16 (s, 4H), 1.13(d, J=12.7 Hz, 7H), 1.02 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ-77.38, -77.71, -77.82, -96.97 (dd, J=59.8, 18.6 Hz), -114.92

Example 152

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(152). Intermediates: P4, A3, and S45. MS (ESI) m/z 1170.6 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.17 (d, J=9.3 Hz, 1H), 8.10 (d, J=2.7 Hz,1H), 7.68 (s, 0H), 7.62 (d, J=8.7 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=8.2Hz, 2H), 7.38 (s, 0H), 7.32 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H),7.11 (d, J=9.9 Hz, 1H), 6.93 (d, J=2.8 Hz, 1H), 6.80 (d, J=9.8 Hz, 1H),6.67 (d, J=8.8 Hz, 1H), 4.96 (dd, J=8.2, 7.0 Hz, 2H), 4.81 (dd, J=8.2,5.1 Hz, 2H), 4.51 (s, 1H), 4.47-4.43 (m, 1H), 4.38 (d, J=13.8 Hz, 2H),4.32-4.27 (m, 1H), 4.15 (d, J=12.2 Hz, 4H), 3.95 (d, J=13.1 Hz, 1H),3.73 (s, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38-3.35 (m, 1H), 3.34-3.32(m, 1H), 2.88 (dd, J=18.8, 5.2 Hz, 3H), 2.78 (dd, J=12.5, 9.0 Hz, 1H),2.56 (s, 3H), 2.25-2.18 (m, 2H), 2.08 (t, J=6.8 Hz, 2H), 1.16 (s, 5H),1.13 (d, J=13.1 Hz, 7H), 1.02 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ-77.39, -77.71, -77.86, -96.97 (dd, J=59.9, 18.5 Hz), -114.92

Example 153

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(153). Intermediates: P7, A3, and S44. MS (ESI) m/z 1170.6 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.29-8.25 (m, 1H), 8.16 (d,J=9.2 Hz, 1H), 8.12 (s, 1H), 7.70-7.60 (m, 2H), 7.55 (td, J=7.4, 3.1 Hz,1H), 7.50 (s, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.34 (s, 1H), 7.24 (dd,J=8.2, 6.7 Hz, 4H), 7.16 (d, J=10.0 Hz, 1H), 6.79 (d, J=9.9 Hz, 1H),4.94 (t, J=7.6 Hz, 2H), 4.79 (dd, J=8.2, 5.2 Hz, 3H), 4.49 (s, 1H),4.47-4.41 (m, 1H), 4.34-4.27 (m, 1H), 4.15 (d, J=8.8 Hz, 1H), 4.09 (d,J=7.1 Hz, 3H), 3.93 (d, J=13.2 Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.57(d, J=13.5 Hz, 2H), 3.51 (s, 0H), 3.47 (dt, J=3.3, 1.7 Hz, 2H), 3.43 (s,1H), 2.99 (s, 0H), 2.91 (d, J=7.8 Hz, 2H), 2.87-2.82 (m, 1H), 2.81-2.73(m, 1H), 2.36 (s, 4H), 2.34 (s, 0H), 2.24 (s, 2H), 2.04-1.91 (m, 0H),1.33-1.26 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.51, -77.71, -96.88 (d,J=59.6 Hz), -115.03, -130.01.

Example 154

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(154). Intermediates: P7, A3, and S46. MS (ESI) m/z 1169.5 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H),8.11 (s, 1H), 7.64 (s, 0H), 7.50 (s, 1H), 7.34 (d, J=7.3 Hz, 2H), 7.24(t, J=7.8 Hz, 4H), 7.11 (d, J=9.9 Hz, 1H), 6.78 (s, 1H), 6.77 (s, 0H),4.96 (t, J=7.6 Hz, 2H), 4.50 (s, 1H), 4.44 (d, J=9.7 Hz, 1H), 4.36-4.27(m, 3H), 4.12 (d, J=10.0 Hz, 4H), 3.94 (d, J=13.2 Hz, 1H), 3.70 (s, 2H),3.68 (s, 3H), 3.66 (s, 3H), 3.38 (s, 1H), 3.34 (s, 3H), 2.94-2.73 (m,4H), 2.44 (s, 3H), 2.27-2.17 (m, 2H), 2.07 (d, J=8.6 Hz, 2H), 1.29 (t,J=7.4 Hz, 0H), 1.20-1.10 (m, 10H), 1.03 (s, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ -77.35, -77.62, -77.67, -96.90 (d, J=59.9 Hz), -115.01.

Example 155

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(155). Intermediates: P7, A3, and S45. MS (ESI) m/z 1169.7 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.12 (s, 2H), 7.64 (s, 0H),7.53 (d, J=8.6 Hz, 1H), 7.49 (s, 1H), 7.37-7.28 (m, 3H), 7.23 (dd,J=15.6, 8.1 Hz, 5H), 4.44 (s, 1H), 4.30 (s, 2H), 4.12 (d, J=12.6 Hz,3H), 3.94 (d, J=13.1 Hz, 1H), 3.68 (s, 4H), 3.66 (s, 4H), 2.90 (d, J=8.2Hz, 2H), 2.79 (d, J=9.9 Hz, 1H), 2.53 (s, 4H), 2.03 (s, 0H), 1.98 (s,1H), 1.28 (d, J=7.2 Hz, 3H), 1.17 (s, 5H), 1.15 (s, 4H), 1.12 (s, 4H),1.03 (s, 4H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -77.36, -77.48, -77.68,-96.91 (d, J=59.7 Hz).

Example 156

Cyclopropyl((2S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(156). Intermediates: P4, A6, and S3. MS (ESI) m/z 1208.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.30 (dd, J=2.3, 0.7 Hz, 1H), 8.21 (d, J=9.4Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 7.81-7.63 (m, 1H), 7.53 (s, 1H), 7.46(d, J=8.3 Hz, 2H), 7.42-7.29 (m, 3H), 7.23 (d, J=8.0 Hz, 3H), 6.94 (d,J=2.8 Hz, 1H), 6.85 (t, J=8.7 Hz, 2H), 5.05-4.90 (m, 3H), 4.48 (d,J=10.0 Hz, 1H), 4.34 (t, J=12.0 Hz, 3H), 4.24-3.84 (m, 7H), 3.75 (s,1H), 3.01-2.66 (m, 5H), 2.22 (dd, J=12.2, 6.4 Hz, 2H), 2.03 (s, 32H),1.29 (s, 1H), 1.19-1.07 (m, 10H), 1.03 (s, 3H), 1.00-0.50 (m, 8H).

Example 157

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(157). Intermediates: P8, A3, and S3. MS (ESI) m/z 1138.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.28-8.25 (m, 1H), 8.07 (s, 1H),7.68 (dd, J=8.9, 2.3 Hz, 1H), 7.66-7.57 (m, 1H), 7.57-7.45 (m, 1H),7.41-7.27 (m, 6H), 7.20 (d, J=8.2 Hz, 2H), 6.90-6.81 (m, 1H), 4.94 (dd,J=8.1, 7.0 Hz, 3H), 4.81 (dd, J=8.1, 4.9 Hz, 3H), 4.53 (d, J=6.3 Hz,1H), 4.45-4.21 (m, 5H), 4.14 (dd, J=4.7, 2.4 Hz, 4H), 4.08-3.83 (m, 3H),3.70 (d, J=24.6 Hz, 2H), 3.60 (s, 3H), 3.38 (dd, J=14.1, 1.7 Hz, 3H),3.29 (p, J=1.6 Hz, 6H), 2.93-2.66 (m, 5H), 2.28-2.02 (m, 3H), 1.11 (d,J=14.3 Hz, 7H), 1.04 (s, 4H), 0.93 (s, 4H).

Example 158

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(158). Intermediates: P6, A3, and S3. MS (ESI) m/z 1120.2 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (dd, J=2.3, 0.7 Hz, 1H), 8.16-7.99 (m,2H), 7.84-7.73 (m, 2H), 7.71-7.37 (m, 4H), 7.37-7.26 (m, 3H), 7.26-7.10(m, 2H), 6.86 (d, J=2.7 Hz, 1H), 6.69 (dd, J=9.0, 0.8 Hz, 1H), 4.76 (t,J=6.4 Hz, 2H), 4.58 (t, J=5.8 Hz, 3H), 4.39 (s, 1H), 4.25 (s, 1H), 4.01(d, J=13.1 Hz, 1H), 3.89 (dt, J=13.1, 4.1 Hz, 4H), 3.85-3.74 (m, 1H),3.60 (s, 3H), 3.12 (dd, J=12.0, 2.2 Hz, 3H), 2.98-2.60 (m, 4H),1.96-1.86 (m, 3H), 1.69 (d, J=7.8 Hz, 2H), 1.11 (d, J=9.3 Hz, 7H), 1.02(s, 3H), 1.00-0.76 (m, 4H).

Example 159

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(159). Intermediates: P4, A3, and S58. MS (ESI) m/z 1102.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 2H), 8.20 (d, J=9.5 Hz, 1H), 8.12(s, 1H), 7.55 (t, J=61.0 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.35 (d, J=7.7Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 6.95 (s, 1H), 4.44 (s, 1H), 4.40 (s,2H), 4.31 (s, 1H), 4.15 (d, J=15.7 Hz, 4H), 3.95 (d, J=12.9 Hz, 1H),3.75 (s, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.50 (s, 2H), 3.03 (d, J=2.8Hz, 3H), 2.90 (t, J=12.3 Hz, 2H), 2.80 (d, J=10.7 Hz, 1H), 1.17 (s, 3H),1.15 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H).

Example 160

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5,14-bis(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2-oxa-4,7,11,12-tetraazatetradecan-14-yl)carbamate(160). Intermediates: P4, A8, and S7. MS (ESI) m/z 1205.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.51 (s, 2H), 8.09 (d, J=2.7 Hz, 1H), 7.52 (t,J=60.0, 59.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H),7.28 (d, J=8.0 Hz, 2H), 6.91 (d, J=2.7 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H),4.81 (dd, J=8.3, 5.1 Hz, 2H), 4.76 (s, 1H), 4.33-4.23 (m, 1H), 4.18-4.12(m, 3H), 4.08 (d, J=18.2 Hz, 2H), 4.03 (d, J=13.5 Hz, 1H), 3.75 (d,J=9.3 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 3H), 3.46 (d, J=14.4 Hz, 2H),3.04-2.85 (m, 3H), 2.79 (d, J=12.7 Hz, 1H), 2.20 (dd, J=8.9, 3.9 Hz,2H), 2.01 (dd, J=12.2, 6.9 Hz, 2H), 1.86-1.65 (m, 12H).

Example 161

tert-butyl3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(161a). MS (ESI) m/z 1200.0 [M+H]+. ¹H NMR (400 MHz, Methanol-d4) δ8.27-8.14 (m, 2H), 8.11 (d, J=2.7 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.53(t, J=59.7 Hz, 2H), 7.45 (d, J=8.2 Hz, 3H), 7.35 (d, J=7.9 Hz, 3H), 7.24(d, J=8.0 Hz, 3H), 7.15 (d, J=9.5 Hz, 1H), 7.08 (d, J=9.3 Hz, 1H), 6.94(d, J=2.8 Hz, 1H), 6.82 (d, J=10.0 Hz, 1H), 4.44 (d, J=11.9 Hz, 4H),4.30 (d, J=10.0 Hz, 1H), 4.14 (d, J=13.3 Hz, 3H), 4.02-3.87 (m, 4H),3.67 (d, J=10.7 Hz, 10H), 3.28-3.18 (m, 3H), 3.03-2.85 (m, 4H),2.82-2.69 (m, 1H), 2.00 (dd, J=9.0, 4.0 Hz, 3H), 1.81 (d, J=7.7 Hz, 3H),1.49 (s, 9H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Methyl((5S,8S,9S,14S)-8-(4-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate2,2,2-trifluoroacetate (161). A solution of 161a (57.8 mg, 0.040 mmol)and trifluoroacetic acid (0.150 ml, 1.96 mmol) in DCM (2 mL) was stirredat room temperature. After 3 h, the reaction mixture was concentratedunder reduced pressure and the residue was purified by HPLC and theproduct lyophilized to afford 161. MS (ESI) m/z 1200.0 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.32-8.26 (m, 1H), 8.18 (d, J=9.4 Hz, 1H), 8.11(d, J=2.7 Hz, 1H), 7.71-7.64 (m, 1H), 7.71-7.36 (m, 1H), 7.45 (d, J=8.1Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 7.15 (d, J=10.0Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 6.82 (t, J=9.9 Hz, 2H), 4.44 (d, J=9.9Hz, 1H), 4.36-4.22 (m, 4H), 4.16 (d, J=28.1 Hz, 4H), 3.94 (d, J=13.2 Hz,1H), 3.67 (d, J=11.1 Hz, 8H), 3.26-3.17 (m, 3H), 2.99-2.69 (m, 5H),2.19-1.96 (m, 5H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s,3H).

Example 162

Synthesis of tert-butyl3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(162a). Intermediates: P7, A3, and S16. MS (ESI) m/z 1199.4 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.53 (d, J=0.7 Hz, 1H), 8.21-8.09 (m, 3H),7.89 (dd, J=9.4, 2.2 Hz, 1H), 7.69-7.32 (m, 2H), 7.35 (s, 1H), 7.24 (dd,J=8.4, 2.4 Hz, 4H), 7.14 (d, J=9.4 Hz, 2H), 4.43 (d, J=4.2 Hz, 3H),4.36-4.23 (m, 1H), 4.23-4.00 (m, 2H), 3.97-3.82 (m, 3H), 3.67 (d, J=9.7Hz, 5H), 3.28 (d, J=9.6 Hz, 2H), 3.00-2.70 (m, 4H), 2.08-1.91 (m, 2H),1.82 (t, J=6.9 Hz, 2H), 1.49 (s, 9H), 1.23-1.08 (m, 9H), 1.03 (s, 3H).

Methyl((5S,8S,9S,14S)-8-(4-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.The title compound 162 was prepared according to the method presentedfor the synthesis of compound 161 but instead utilizing 162a. MS (ESI)m/z 1099.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.18(d, J=2.3 Hz, 1H), 8.08 (d, J=9.4 Hz, 1H), 8.03 (s, 1H), 7.63-7.55 (m,1H), 7.41 (s, 1H), 7.29-7.20 (m, 2H), 7.14 (dd, J=14.9, 8.2 Hz, 4H),6.73 (t, J=9.6 Hz, 2H), 4.34 (d, J=9.7 Hz, 1H), 4.28-4.13 (m, 4H),4.13-3.91 (m, 4H), 3.83 (d, J=13.1 Hz, 1H), 3.58 (d, J=10.5 Hz, 7H),3.14 (d, J=13.5 Hz, 2H), 2.75 (dd, J=47.8, 9.1 Hz, 4H), 2.12-1.85 (m,3H), 1.16-0.97 (m, 9H), 0.94 (s, 3H).

Example 163

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(163). Intermediates: P4, A3, and S17. MS (ESI) m/z 1141.7 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.17-8.03 (m, 2H), 8.01 (d, J=2.7 Hz, 1H),7.66 (d, J=8.9 Hz, 1H), 7.44 (t, J=59.8 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H),7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.06 (d, J=9.8 Hz, 1H),6.85 (d, J=2.8 Hz, 1H), 6.72 (d, J=9.9 Hz, 1H), 6.50 (d, J=8.9 Hz, 1H),4.90-4.82 (m, 1H), 4.49-4.34 (m, 6H), 4.28 (s, 4H), 4.21 (d, J=10.0 Hz,1H), 4.05 (d, J=13.0 Hz, 2H), 3.85 (d, J=13.2 Hz, 1H), 3.64 (s, 2H),3.59 (s, 3H), 3.57 (s, 3H), 2.88-2.74 (m, 3H), 2.74-2.63 (m, 1H), 1.06(s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 164

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(164). Intermediates: P4, A3, and S18. MS (ESI) m/z 1114.3 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.19-8.05 (m, 2H), 8.01 (d, J=2.7 Hz, 1H),7.61 (dd, J=8.9, 2.2 Hz, 1H), 7.44 (t, J=59.8 Hz, 1H), 7.36 (d, J=8.2Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.05 (d, J=9.9Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 6.72 (d, J=10.0 Hz, 1H), 6.64 (d, J=8.9Hz, 1H), 4.35 (d, J=9.8 Hz, 1H), 4.21 (d, J=10.0 Hz, 1H), 4.05 (d,J=12.6 Hz, 2H), 3.85 (d, J=13.1 Hz, 2H), 3.65 (s, 1H), 3.58 (d, J=10.7Hz, 6H), 3.36 (d, J=14.9 Hz, 2H), 2.84 (dd, J=18.9, 9.2 Hz, 5H), 2.70(d, J=10.2 Hz, 1H), 1.06 (d, J=6.3 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 165

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((3aR,6aS)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(165). Intermediates: P4, A3, and S19. MS (ESI) m/z 1156.2 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.09 (d, J=2.3 Hz, 2H), 8.01 (d, J=2.7 Hz,1H), 7.72 (dd, J=8.9, 2.2 Hz, 1H), 7.44 (t, J=59.8 Hz, 1H), 7.36 (d,J=8.2 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.05 (d,J=9.9 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 6.81-6.67 (m, 2H), 4.63 (dd,J=8.3, 5.1 Hz, 2H), 4.46-4.30 (m, 2H), 4.21 (d, J=10.0 Hz, 1H), 4.05 (d,J=13.3 Hz, 2H), 3.85 (d, J=13.2 Hz, 1H), 3.64 (d, J=4.3 Hz, 6H), 3.59(s, 3H), 3.57 (s, 3H), 3.32 (s, 3H), 2.87-2.62 (m, 4H), 1.06 (d, J=6.2Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 166

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-((6-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(166). Intermediates: P7, A3, and S22. MS (ESI) m/z 1142.5 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.44 (d, J=0.7 Hz, 1H), 8.20 (s, 1H), 8.07(d, J=9.5 Hz, 1H), 8.06-8.02 (m, 1H), 7.67-7.50 (m, 1H), 7.50-7.43 (m,0H), 7.41 (s, 0H), 7.29-7.20 (m, 2H), 7.14 (dd, J=13.7, 8.3 Hz, 3H),6.73 (dd, J=18.5, 9.6 Hz, 1H), 4.34 (t, J=5.2 Hz, 3H), 4.30-4.15 (m,3H), 4.13-3.94 (m, 3H), 3.84 (d, J=13.2 Hz, 1H), 3.58 (d, J=10.5 Hz,6H), 3.17 (d, J=2.4 Hz, 1H), 2.91-2.64 (m, 3H), 2.14 (d, J=11.4 Hz, 2H),1.95 (d, J=8.6 Hz, 1H), 1.37 (d, J=6.4 Hz, 6H), 1.12-0.97 (m, 9H), 0.94(s, 3H).

Example 167

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(167). Intermediates: P7, A3, and S21. MS (ESI) m/z 1128.6 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.44 (d, J=0.7 Hz, 1H), 8.19 (d, J=2.2 Hz,1H), 8.06 (d, J=21.7 Hz, 2H), 7.63-7.53 (m, 1H), 7.41 (s, 1H), 7.28-7.21(m, 2H), 7.14 (dd, J=13.9, 8.2 Hz, 4H), 6.73 (dd, J=18.8, 9.5 Hz, 2H),4.42-4.30 (m, 1H), 4.30-4.18 (m, 3H), 4.13 (d, J=4.3 Hz, 2H), 4.02 (d,J=12.6 Hz, 2H), 3.84 (d, J=13.2 Hz, 1H), 3.58 (d, J=10.5 Hz, 7H), 3.09(q, J=7.3 Hz, 2H), 2.92-2.72 (m, 3H), 2.72-2.61 (m, 1H), 2.24-2.13 (m,2H), 1.96 (d, J=8.7 Hz, 2H), 1.32 (t, J=7.3 Hz, 3H), 1.11-0.98 (m, 9H),0.94 (s, 3H).

Example 168

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(168). Intermediates: P7, A3, and S20. MS (ESI) m/z 1113.4 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.45 (d, J=0.7 Hz, 1H), 8.24-8.16 (m, 1H),8.08 (d, J=9.3 Hz, 1H), 8.03 (s, 1H), 7.63-7.54 (m, 1H), 7.41 (s, 1H),7.28-7.21 (m, 2H), 7.14 (dd, J=14.5, 8.2 Hz, 5H), 6.74 (dd, J=15.5, 9.4Hz, 2H), 4.34 (d, J=9.9 Hz, 1H), 4.24 (dd, J=17.7, 11.9 Hz, 3H), 4.02(d, J=13.4 Hz, 4H), 3.83 (d, J=13.2 Hz, 1H), 3.58 (d, J=10.4 Hz, 7H),3.16 (s, 1H), 3.06-2.96 (m, 0H), 2.85-2.58 (m, 6H), 2.31-2.13 (m, 2H),2.05-1.89 (m, 2H), 1.13-0.96 (m, 9H), 0.94 (s, 3H).

Example 169

oxetan-3-yl((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-(2S,3S)-2-hydroxy-4-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(169). Intermediates: P4, A4, and S3. MS (ESI) m/z 1239.3 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.13 (d, J=2.3 Hz, 1H), 8.09 (d, J=9.4 Hz, 1H),8.02 (d, J=2.8 Hz, 1H), 7.52 (dd, J=8.9, 2.4 Hz, 1H), 7.45 (t, J=59.9Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.9Hz, 2H), 6.85 (d, J=2.8 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.29 (dp,J=17.2, 5.7 Hz, 2H), 4.76-4.73 (m, 4H), 4.67 (t, J=6.4 Hz, 2H), 4.56(ddd, J=10.3, 7.3, 5.4 Hz, 2H), 4.52-4.42 (m, 4H), 4.32 (s, 1H), 4.20(s, 1H), 4.11-4.00 (m, 2H), 3.90-3.76 (m, 3H), 3.77-3.60 (m, 2H),3.08-2.97 (m, 2H), 2.89-2.75 (m, 3H), 2.73-2.63 (m, 1H), 1.90-1.81 (m,2H), 1.68-1.56 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.95(s, 3H).

Example 170

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(170). Intermediates: P13, A3, and S3. MS (ESI) m/z 1146.0 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.29 (dd, J=2.3, 0.8 Hz, 1H), 8.18 (d,J=9.2 Hz, 1H), 7.70 (td, J=4.9, 4.4, 2.3 Hz, 2H), 7.39-7.27 (m, 4H),7.22 (d, J=8.1 Hz, 2H), 7.16 (d, J=9.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H),6.80 (d, J=9.9 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.96 (dd, J=8.2, 7.0 Hz,2H), 4.81 (dd, J=8.3, 5.1 Hz, 2H), 4.46-4.41 (m, 1H), 4.39-4.33 (m, 1H),4.31 (d, J=10.0 Hz, 1H), 4.19-4.07 (m, 4H), 3.93 (d, J=13.2 Hz, 1H),3.76-3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.40-3.34 (m, 2H),2.95-2.70 (m, 4H), 2.30-2.18 (m, 2H), 2.12-2.01 (m, 2H), 1.22-1.04 (m,13H), 1.02 (s, 3H).

Example 171

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(171). Intermediates: P4, A3, and S7. MS (ESI) m/z 1156.4 [M+H]+. 1H NMR(400 MHz, Methanol-d4) δ 8.43 (s, 2H), 8.08 (d, J=9.4 Hz, 1H), 8.01 (d,J=2.8 Hz, 1H), 7.44 (d, J=59.8 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.25 (d,J=7.9 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.03 (d, J=9.9 Hz, 1H), 6.84 (d,J=2.7 Hz, 1H), 6.71 (d, J=9.9 Hz, 1H), 4.87 (t, J=7.6 Hz, 2H), 4.72 (dd,J=8.2, 4.9 Hz, 2H), 4.67 (s, 1H), 4.42-4.29 (m, 1H), 4.25-4.18 (m, 1H),4.11-3.98 (m, 4H), 3.85 (d, J=13.1 Hz, 1H), 3.69-3.62 (m, 2H), 3.59 (s,3H), 3.57 (s, 3H), 3.41-3.28 (m, 2H), 2.87-2.75 (m, 3H), 2.68 (dd,J=12.6, 9.1 Hz, 1H), 2.18-2.06 (m, 2H), 1.95-1.83 (m, 2H), 1.07 (s, 3H),1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 172

Methyl((5S,8S,9S,14S)-8-(4-((2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(172). Intermediates: P4, A3, and S36. MS (ESI) m/z 1100.4 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.41 (s, 2H), 8.08 (d, J=9.2 Hz, 1H), 8.01(d, J=2.7 Hz, 1H), 7.44 (d, J=59.8 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.25(d, J=7.9 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.84(d, J=2.8 Hz, 1H), 6.70 (d, J=10.2 Hz, 1H), 4.66-4.57 (m, 2H), 4.35 (d,J=9.6 Hz, 1H), 4.26-4.17 (m, 1H), 4.12-3.96 (m, 5H), 3.85 (d, J=13.2 Hz,1H), 3.69-3.62 (m, 2H), 3.59 (s, 3H), 3.57 (s, 3H), 3.25 (s, 1H),2.87-2.61 (m, 4H), 2.05-1.96 (m, 2H), 1.90-1.82 (m, 2H), 1.07 (s, 3H),1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

Example 173

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(173). Intermediates: P4, A3, and S6. MS (ESI) m/z 1141.5 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.29-8.23 (m, 1H), 8.17 (d, J=9.4 Hz, 1H), 8.10(d, J=2.7 Hz, 1H), 7.69 (dd, J=8.6, 2.1 Hz, 1H), 7.53 (t, J=59.7 Hz,1H), 7.45 (d, J=8.2 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.1 Hz,2H), 7.13 (d, J=9.8 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.80 (d, J=10.2 Hz,1H), 6.71-6.63 (m, 1H), 5.07-5.01 (m, 1H), 4.72-4.68 (m, 1H), 4.64-4.54(m, 2H), 4.52-4.49 (m, 1H), 4.47-4.41 (m, 1H), 4.30 (d, J=10.0 Hz, 1H),4.20-4.08 (m, 2H), 3.94 (d, J=13.1 Hz, 1H), 3.79 (d, J=11.0 Hz, 1H),3.72 (d, J=11.7 Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 2.93-2.82 (m, 3H),2.81-2.73 (m, 1H), 2.33 (s, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.11 (s,3H), 1.02 (s, 3H).

Example 174

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(174). Intermediates: P4, A3, and S30. MS (ESI) m/z 1141.6 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.25 (dd, J=2.2, 0.8 Hz, 1H), 8.17 (d,J=9.4 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.74-7.68 (m, 1H), 7.53 (t,J=59.6 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.22 (d,J=8.1 Hz, 2H), 7.13 (d, J=9.9 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 6.80 (d,J=9.9 Hz, 1H), 6.71-6.61 (m, 1H), 5.05 (s, 1H), 4.99-4.93 (m, 1H), 4.70(dd, J=8.4, 4.5 Hz, 1H), 4.64-4.53 (m, 2H), 4.51 (s, 1H), 4.44 (d, J=9.8Hz, 1H), 4.30 (d, J=10.0 Hz, 1H), 4.18-4.10 (m, 2H), 3.94 (d, J=13.1 Hz,1H), 3.79 (dd, J=11.9, 2.2 Hz, 1H), 3.76-3.70 (m, 1H), 3.69 (s, 3H),3.66 (s, 3H), 2.94-2.73 (m, 4H), 2.33 (s, 2H), 1.16 (s, 3H), 1.14 (s,3H), 1.11 (s, 3H), 1.02 (s, 3H).

Example 175

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(175). Intermediates: P28, A3, and S4. MS (ESI) m/z 1102.4 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.66 (d, J=5.0 Hz, 1H), 8.33 (d, J=2.2 Hz,1H), 8.14 (d, J=9.4 Hz, 1H), 8.03-7.88 (m, 2H), 7.74 (dd, J=8.7, 2.3 Hz,1H), 7.60 (d, J=8.5 Hz, 2H), 7.46 (t, J=6.1 Hz, 1H), 7.34 (d, J=7.8 Hz,2H), 7.23 (d, J=7.9 Hz, 2H), 7.11 (d, J=9.4 Hz, 1H), 6.78 (d, J=8.8 Hz,2H), 4.97 (s, 3H), 4.62 (dd, J=8.1, 4.1 Hz, 2H), 4.44 (d, J=8.2 Hz, 1H),4.34-4.26 (m, 1H), 4.26-4.07 (m, 4H), 3.98 (d, J=13.1 Hz, 2H), 3.79-3.71(m, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 2.99-2.85 (m, 3H), 2.84-2.74 (m,1H), 2.11 (d, J=11.2 Hz, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H),1.03 (s, 3H).

Example 176

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(176). Intermediates: P4, A3, and S4. MS (ESI) m/z 1141.8 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.33 (d, J=2.1 Hz, 1H), 8.14 (d, J=9.3 Hz, 1H),8.10 (d, J=2.8 Hz, 1H), 7.74 (dd, J=8.8, 2.2 Hz, 1H), 7.53 (t, J=59.8Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.09 (d, J=10.3 Hz, 1H), 6.93 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.8Hz, 2H), 5.07-4.91 (m, 3H), 4.61 (dd, J=8.2, 4.1 Hz, 2H), 4.44 (d, J=9.9Hz, 1H), 4.31 (d, J=10.0 Hz, 1H), 4.23-4.06 (m, 3H), 3.95 (d, J=13.3 Hz,1H), 3.70 (s, 3H), 3.66 (s, 3H), 2.95-2.70 (m, 4H), 2.10 (d, J=11.1 Hz,1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).

Example 177

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(177). Intermediates: P28, A3, and S3. MS (ESI) m/z 1115.9 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.69-8.60 (m, 1H), 8.18 (d, J=9.3 Hz, 1H),7.94 (q, J=7.9 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.44 (t, J=5.7 Hz, 1H),7.39 (d, J=8.8 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H),7.17 (d, J=10.7 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.79 (d, J=10.0 Hz,1H), 5.01-4.92 (m, 3H), 4.84-4.76 (m, 2H), 4.44 (d, J=9.9 Hz, 1H), 4.31(d, J=10.0 Hz, 1H), 4.23-4.10 (m, 4H), 3.97 (d, J=13.1 Hz, 1H), 3.85 (d,J=13.0 Hz, 2H), 3.79-3.72 (m, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 2.93-2.84(m, 3H), 2.83-2.75 (m, 1H), 2.21 (q, J=11.1, 10.5 Hz, 4H), 1.27 (d,J=5.7 Hz, 1H), 1.16 (s, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).¹⁹F NMR (377 MHz, Methanol-d4) δ -77.39, -77.73, -77.85, -114.65.

Example 178

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(178). Intermediates: P4, A3, and S3. MS (ESI) m/z 1154.4 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.07 (d, J=9.4 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H),7.44 (t, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.21 (d,J=7.9 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.89-6.82 (m, 3H), 4.86 (t, J=7.5Hz, 2H), 4.72-4.64 (m, 2H), 4.35 (d, J=6.4 Hz, 1H), 4.25-4.16 (m, 1H),4.11-3.95 (m, 3H), 3.85 (d, J=12.5 Hz, 1H), 3.80-3.70 (m, 1H), 3.68-3.62(m, 1H), 3.60 (s, 3H), 3.57 (s, 3H), 2.85-2.63 (m, 4H), 2.18-1.99 (m,4H), 1.22-1.18 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.40, -77.49, -77.73, -96.96(dd, J=60.0, 18.7 Hz), -114.92.

Example 179

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(179). Intermediates: P28, A3, and S1. MS (ESI) m/z 1133.1 [M+H]+. ¹HNMR (400 MHz, Methanol-d4) δ 8.66 (d, J=4.8 Hz, 1H), 8.21-8.10 (m, 2H),8.02-7.82 (m, 3H), 7.60 (d, J=8.6 Hz, 2H), 7.46 (t, J=6.3 Hz, 1H), 7.36(d, J=7.9 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.19 (d, J=9.4 Hz, 1H),4.82-4.76 (m, 2H), 4.66-4.58 (m, 2H), 4.51-4.41 (m, 1H), 4.35-4.27 (m,1H), 4.23-4.13 (m, 2H), 4.13-3.89 (m, 7H), 3.78-3.72 (m, 2H), 3.69 (s,3H), 3.68-3.65 (m, 3H), 3.63 (s, 3H), 3.18-3.08 (m, 2H), 3.00-2.84 (m,3H), 2.84-2.74 (m, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.37, -77.71, -77.99,-114.58.

Example 180

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(180). Intermediates: P4, A3, and S1. MS (ESI) m/z 1171.8 [M+H]+. ¹H NMR(400 MHz, Methanol-d4) δ 8.20-8.13 (m, 2H), 8.10 (d, J=2.7 Hz, 1H), 7.87(d, J=8.7 Hz, 1H), 7.60 (t, J=59.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.36(d, J=8.0 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.15 (d, J=9.5 Hz, 1H), 6.93(d, J=2.7 Hz, 1H), 4.80-4.75 (m, 1H), 4.74-4.67 (m, 1H), 4.62 (t, J=5.7Hz, 2H), 4.46-4.40 (m, 1H), 4.32-4.25 (m, 1H), 4.21-4.00 (m, 6H),3.99-3.89 (m, 3H), 3.78-3.71 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.12(d, J=4.9 Hz, 2H), 2.98-2.72 (m, 4H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11(s, 3H), 1.03 (s, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71,-77.85, -96.97 (dd, J=59.7, 19.1 Hz), -114.93.

Example 181

Synthesis of tert-butyl2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate(181a). The title compound 181a was prepared according to the methodpresented for the synthesis of compound 1a but instead utilizing 12a andP4. MS (ESI) m/z 764.1 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.09 (d,J=2.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.53 (t, J=59.8 Hz, 1H),7.51-7.35 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.93 (d, J=2.7 Hz, 1H), 4.03(d, J=26.8 Hz, 2H), 3.70 (d, J=8.2 Hz, 1H), 3.57 (d, J=9.0 Hz, 1H), 2.79(tdd, J=20.0, 11.2, 6.9 Hz, 2H), 1.37 (s, 8H), 1.31 (s, 7H). ¹⁹F NMR(377 MHz, Methanol-d4) δ -96.90 (d, J=59.8 Hz), -115.32

Synthesis of tert-butyl((6S,11S,12S,15S)-9-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17-trifluoro-11-hydroxy-12-(4-iodobenzyl)-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,9,13-tetraazaheptadecan-15-yl)carbamate(181b). The title compound 181b was prepared according to the methodpresented for the synthesis of intermediate I2 but instead utilizing181a and A1. MS (ESI) m/z 1098.6 [M+H]⁺.

Synthesis of tert-butyl((6S,11S,12S,15S)-9-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17-trifluoro-11-hydroxy-2,2,16,16-tetramethyl-12-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,9,13-tetraazaheptadecan-15-yl)carbamate(181c) The title compound 181c was prepared according to the methodpresented for the synthesis of compound 133 but instead utilizing 181band S3. MS (ESI) m/z 1239.9 [M+H]⁺.

(2S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-3-hydroxy-1-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)pethynyl)phenyl)butan-2-yl)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanamide(181). To a solution of 181c (355 mg, 0.29 mmol) in DCM (10 mL) wasadded trifluoroacetic acid (2 mL), the mixture was stirred and after 18h, the reaction mixture was concentrated under reduced pressure and thecrude material was dissolved in DMF (3 mL) and HATU (35.28 mg, 0.16mmol), N,N-diisopropylethylamine (0.13 ml, 0.74 mmol) was added followedby propionic acid (0.01 ml, 0.16 mmol). The reaction was stirred atstirred at room temperature overnight. The reaction mixture was purifiedby HPLC to afford 181. MS (ESI) m/z 1152.1 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d4) δ 8.20 (dd, J=2.3, 0.7 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H),7.74-7.37 (m, 4H), 7.37-7.23 (m, 2H), 7.23-7.12 (m, 2H), 6.95 (d, J=2.8Hz, 1H), 6.70 (dd, J=9.1, 0.8 Hz, 1H), 4.83-4.71 (m, 3H), 4.66 (s, 1H),4.59 (dd, J=6.3, 5.4 Hz, 3H), 4.23-4.13 (m, 2H), 4.00-3.84 (m, 4H),3.84-3.70 (m, 1H), 3.13 (dd, J=12.0, 2.2 Hz, 3H), 2.95-2.71 (m, 4H),2.21 (ttd, J=7.5, 5.0, 2.3 Hz, 4H), 1.97-1.90 (m, 2H), 1.70 (d, J=7.8Hz, 2H), 1.18 (d, J=9.3 Hz, 7H), 1.16-1.00 (m, 13H).

Example 182

(2S)-2-acetamido-N-((2S,3S)-4-(2-(S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide(182). The title compound 182 was prepared according to the methodpresented for the synthesis of compound 181 but instead utilizingIntermediates: P4, A1, S3 and acetic acid. MS (ESI) m/z 1123.9 [M+H]⁺.¹H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J=2.3, 0.7 Hz, 1H), 8.09 (d,J=2.7 Hz, 1H), 7.72-7.35 (m, 4H), 7.35-7.24 (m, 2H), 7.20-7.11 (m, 2H),6.94 (d, J=2.8 Hz, 1H), 6.69 (dd, J=9.0, 0.8 Hz, 1H), 4.76 (dd, J=12.8,6.4 Hz, 3H), 4.63 (d, J=1.4 Hz, 1H), 4.57 (dd, J=6.3, 5.4 Hz, 3H), 4.15(d, J=13.4 Hz, 2H), 3.98-3.65 (m, 5H), 3.11 (dd, J=12.0, 2.2 Hz, 3H),2.98-2.67 (m, 4H), 2.13 (d, J=10.3 Hz, 0H), 1.98-1.83 (m, 9H), 1.68 (d,J=7.8 Hz, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.12 (s, 3H), 1.04 (s, 3H), 0.88(d, J=6.7 Hz, 0H).

Example 183

Synthesis of (9H-fluoren-9-yl)methyl((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(183a) The title compound 183a was prepared according to the methodpresented for the synthesis of compound 133a but instead utilizing I4and P4. MS (ESI) m/z 999.3 [M+H]⁺.

Synthesis of (9H-fluoren-9-yl)methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(183b) The title compound 183b was prepared according to the methodpresented for the synthesis of compound 133b but instead utilizing 4aand A3. MS (ESI) m/z 1124.6 [M+H]⁺.

Synthesis of methyl((2S)-1-((2S,3S)-4-(2-((S)-2-amino-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)pethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(183c) The title compound 183c was prepared according to the methodpresented for the synthesis of compound 133 but instead utilizing 183band S3. MS (ESI) m/z 1043.5 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.29(dd, J=2.3, 0.7 Hz, 1H), 8.14-8.07 (m, 2H), 7.75-7.65 (m, 1H), 7.53 (d,J=59.8 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H),7.25-7.18 (m, 2H), 6.94 (d, J=2.8 Hz, 1H), 6.86 (dd, J=9.0, 0.9 Hz, 1H),6.78 (d, J=9.9 Hz, 1H), 4.99-4.93 (m, 3H), 4.84 (d, J=5.2 Hz, 1H), 4.82(d, J=5.0 Hz, 1H), 4.54 (s, 1H), 4.42-4.30 (m, 3H), 4.26-4.06 (m, 5H),3.81 (t, J=6.6 Hz, 1H), 3.65 (s, 1H), 3.45-3.36 (m, 3H), 2.97-2.76 (m,4H), 2.28-2.19 (m, 2H), 2.11-2.03 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H),0.97 (s, 9H).

Synthesis of methyl((2S)-1-((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(183) To a solution of 183c (45 mg, 0.33 mmol) in DCM (1 mL) was addedEt₃N (0.03 ml, 0.23 mmol) at 5° C., cyclopropanecarbonyl chloride (3.54μl, 0.39 mmol) was added and the mixture was stirred for 10 min, thendiluted with MeOH, concentrated under reduced pressure and the residuewas purified by HPLC to afford 183. MS (ESI) m/z 1111.5 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.35-8.26 (m, 1H), 8.18 (d, J=9.4 Hz, 1H), 8.11(d, J=2.7 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.8, 2.3 Hz, 1H),7.53 (t, J=59.7 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),7.22 (d, J=8.1 Hz, 2H), 6.94 (d, J=2.8 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H),6.78 (d, J=9.9 Hz, 1H), 5.03-4.94 (m, 2H), 4.84-4.77 (m, 3H), 4.44 (d,J=9.9 Hz, 1H), 4.41-4.31 (m, 1H), 4.21-4.06 (m, 5H), 3.96 (d, J=13.1 Hz,1H), 3.81-3.72 (m, 1H), 3.70 (s, 3H), 3.39 (s, 1H), 2.91 (d, J=7.7 Hz,2H), 2.88-2.73 (m, 2H), 2.29-2.19 (m, 2H), 2.15-2.04 (m, 2H), 1.74-1.67(m, 1H), 1.31 (t, J=7.5 Hz, 1H), 1.14 (s, 3H), 1.10 (s, 3H), 0.89 (s,9H), 0.75 (dd, J=8.2, 3.6 Hz, 2H).

Example 184

methyl((2S)-1-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-3,3-dimethyl-2-((oxetan-3-yloxy)carbonyl)amino)butanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate.Intermediates: P4, A3, S3 and 4-nitrophenyl oxetan-3-yl carbonate. MS(ESI) m/z 1143.6 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.25-8.19 (m,1H), 8.09 (d, J=9.3 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.65-7.59 (m, 1H),7.44 (t, J=59.7 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.23 (d, J=7.9 Hz, 3H),7.13 (d, J=8.0 Hz, 3H), 6.85 (d, J=2.7 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H),6.71 (d, J=9.6 Hz, 1H), 4.87 (t, J=7.6 Hz, 3H), 4.76-4.68 (m, 2H), 4.51(dt, J=23.0, 6.4 Hz, 2H), 4.31-4.22 (m, 2H), 4.12-3.99 (m, 5H), 3.87 (d,J=13.1 Hz, 1H), 3.70-3.62 (m, 2H), 3.59 (s, 3H), 3.30 (s, 1H), 2.89-2.60(m, 5H), 2.18-2.10 (m, 2H), 2.03-1.95 (m, 2H), 1.24-1.17 (m, 2H), 1.05(s, 3H), 1.01 (s, 3H), 0.78 (s, 9H).

Example 185

Methyl((2S)-1-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)pethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate.Intermediates: P4, A3, S3 and propionyl chloride MS (ESI) m/z 1099.6M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.22-8.18 (m, 1H), 8.08 (d, J=9.2Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.61 (dd, J=8.9, 2.3 Hz, 1H), 7.56 (d,J=9.2 Hz, 1H), 7.43 (d, J=59.9 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d,J=8.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H), 6.77 (d,J=8.9 Hz, 1H), 6.69 (d, J=9.9 Hz, 1H), 4.87 (dd, J=8.1, 6.9 Hz, 2H),4.73-4.69 (m, 2H), 4.36-4.31 (m, 1H), 4.30-4.19 (m, 3H), 4.09-4.02 (m,4H), 4.01-3.96 (m, 1H), 3.86 (d, J=13.2 Hz, 1H), 3.68-3.62 (m, 1H), 3.59(s, 3H), 3.31-3.24 (m, 2H), 2.84-2.64 (m, 3H), 2.18-2.07 (m, 2H),2.03-1.94 (m, 2H), 1.04 (s, 3H), 1.03-0.97 (m, 6H), 0.77 (s, 9H).

Example 186

Methyl((2S)-1-((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)pethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(186). Intermediates: P4, A3, S7 and cyclopropanecarboxylic acid. MS(ESI) m/z 1167.0 M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 2H),8.22 (d, J=9.6 Hz, 1H), 8.14 (d, J=9.4 Hz, 1H), 8.09 (d, J=2.7 Hz, 1H),7.52 (t, J=59.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H),7.23 (d, J=8.0 Hz, 2H), 6.92 (d, J=2.8 Hz, 1H), 6.75 (d, J=9.9 Hz, 1H),4.96 (t, J=7.6 Hz, 2H), 4.82-4.77 (m, 2H), 4.75 (s, 1H), 4.65 (d, J=9.7Hz, 1H), 4.43 (d, J=9.9 Hz, 1H), 4.23-4.07 (m, 4H), 3.92 (d, J=13.0 Hz,1H), 3.74 (d, J=8.6 Hz, 1H), 3.69 (s, 3H), 3.45 (d, J=14.5 Hz, 2H),2.97-2.82 (m, 3H), 2.81-2.69 (m, 1H), 2.27-2.10 (m, 2H), 2.03-1.89 (m,2H), 1.74-1.63 (m, 1H), 1.19 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.06(s, 3H), 0.97-0.88 (m, 1H), 0.87-0.70 (m, 3H).

Example 187

Synthesis of cyclopropyl((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(187a). The title compound 187a was prepared according to the methodpresented for the synthesis of compound 133a but instead utilizing I5and P4. MS (ESI) m/z 861.1 [M+H]⁺.

Synthesis of cyclopropyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(187b). The title compound 187b was prepared according to the methodpresented for the synthesis of compound 133b but instead utilizing 5a.MS (ESI) m/z 986.5 [M+H]⁺.

Synthesis of cyclopropyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(187). The title compound 187 was prepared according to the methodpresented for the synthesis of compound 133 but instead utilizing 187band S3. MS (ESI) m/z 1127.4 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.33-8.25 (m, 1H), 8.18 (d, J=9.3 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H),7.74-7.66 (m, 1H), 7.53 (d, J=59.7 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.32(d, J=8.0 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 6.93 (d, J=2.7 Hz, 1H), 6.86(d, J=8.9 Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.96 (t, J=7.5 Hz, 2H), 4.81(dd, J=8.2, 5.2 Hz, 2H), 4.44 (d, J=10.0 Hz, 1H), 4.35 (d, J=13.6 Hz,2H), 4.23-4.06 (m, 4H), 4.03-3.92 (m, 2H), 3.82-3.74 (m, 1H), 3.69 (s,3H), 3.40-3.33 (m, 2H), 2.97-2.73 (m, 3H), 2.31-2.18 (m, 2H), 2.11-2.04(m, 2H), 1.16-1.12 (m, 3H), 1.10 (s, 3H), 0.85 (s, 9H), 0.68-0.58 (m,4H).

Example 188

Synthesis of methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(188) A suspension of S6a (59.8 mg, 0.167 mmol),bis(neopentylglycoloato)diboron (38 mg, 0.168 mmol), potassiumpropionate (44.5 mg, 0.397 mmol) and Pd(PPh₃)₂Cl₂ (2.8 mg, 0.004 mmol)in 2-MeTHF (1 mL) was degassed with argon for 15 min, then heated at 90°C. overnight. Cooled to room temperature, then added 1M PotassiumPhosphate in H₂O (0.39 ml) and degassed for 5 min. Added Pd(tBu₂PPh)₂Cl₂(4.5 mg, 0.007 mmol) and 1a (100 mg, 0.1 mmol) in 2-Me THF (1 mL) anddegassed an additional 5 min. Heated at 65° C. The reaction mixture wascooled to room temperature. Diluted with EtOAc and washed with brine.The separated organic layer was dried over Na₂SO₄ and concentrated undervacuum, the residue was purified by HPLC and the product was lyophilizedto afford 188. MS (ESI) m/z 1131.2 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 8.19 (s, 1H), 8.10 (d, J=9.3 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.64 (d,J=2.5 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 7.05 (d,J=9.9 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.76 (d, J=9.8 Hz, 1H), 6.65 (d,J=2.5 Hz, 1H), 6.32-5.96 (m, 1H), 4.96 (s, 1H), 4.61 (dd, J=8.2, 4.7 Hz,1H), 4.58-4.49 (m, 3H), 4.45 (dd, J=14.2, 4.8 Hz, 1H), 4.37 (s, 1H),4.21 (d, J=9.9 Hz, 1H), 4.04 (d, J=13.0 Hz, 2H), 3.84 (d, J=13.2 Hz,1H), 3.74 (d, J=11.9 Hz, 1H), 3.67 (d, J=11.5 Hz, 2H), 3.54 (s, 4H),3.47 (s, 3H), 2.92-2.73 (m, 4H), 2.73-2.62 (m, 1H), 2.24 (s, 2H), 1.05(d, J=4.5 Hz, 7H), 1.01 (s, 3H), 0.92 (s, 3H).

Example 189

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(189). Intermediates: I2, P1 and S7a. MS (ESI) m/z 1132.9 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.65 (s, 2H), 8.19 (d, J=7.9 Hz, 2H), 8.02 (s,1H), 7.59 (t, J=60.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.17 (d, J=10.0Hz, 1H), 6.88 (d, J=9.9 Hz, 0H), 4.96 (t, J=7.6 Hz, 2H), 4.83 (dd,J=8.3, 5.3 Hz, 2H), 4.47 (d, J=7.2 Hz, 2H), 4.39-4.23 (m, 1H), 4.13 (d,J=13.3 Hz, 5H), 3.93 (d, J=13.3 Hz, 1H), 3.75 (s, 1H), 3.65 (s, 3H),3.56 (s, 3H), 3.47 (d, J=14.5 Hz, 2H), 3.03-2.73 (m, 4H), 2.29-2.11 (m,2H), 2.01 (d, J=9.1 Hz, 2H), 1.14 (d, J=5.2 Hz, 6H), 1.10 (s, 3H), 1.02(s, 3H).

Example 190

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(190). Intermediates: I3, P1 and S7a. MS (ESI) m/z 1079.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.56 (s, 2H), 8.20-8.03 (m, 2H), 7.92 (d, J=1.3Hz, 1H), 7.49 (t, J=59.9 Hz, 1H), 7.31 (dd, J=9.9, 8.2 Hz, 4H), 7.22 (d,J=7.8 Hz, 2H), 6.79 (d, J=10.0 Hz, 0H), 4.87 (t, J=7.6 Hz, 2H),4.75-4.63 (m, 2H), 4.54-4.34 (m, 1H), 4.11-3.95 (m, 3H), 3.86 (d, J=13.2Hz, 1H), 3.66 (s, 1H), 3.54 (s, 3H), 3.47 (s, 2H), 3.37 (d, J=14.4 Hz,2H), 2.83 (t, J=8.0 Hz, 2H), 2.71 (d, J=8.8 Hz, 2H), 2.20-2.07 (m, 2H),1.92 (d, J=8.9 Hz, 2H), 1.04 (s, 3H), 1.00 (s, 3H), 0.75 (s, 8H).

Example 191

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.(191) Intermediates: I2, P10 and S6a. MS (ESI) m/z 1132.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.64 (s, 2H), 8.14 (d, J=9.4 Hz, 1H), 7.87 (d,J=8.6 Hz, 0H), 7.73 (d, J=2.4 Hz, 1H), 7.55 (dt, J=15.4, 7.4 Hz, 1H),7.50-7.21 (m, 6H), 7.09 (d, J=9.9 Hz, 1H), 6.83 (d, J=9.8 Hz, 1H), 6.73(d, J=2.4 Hz, 1H), 6.21 (tt, J=55.3, 3.9 Hz, 1H), 5.18 (s, 1H),5.02-4.89 (m, 2H), 4.73 (d, J=5.1 Hz, 1H), 4.59 (td, J=14.1, 13.7, 6.4Hz, 3H), 4.52 (s, 1H), 4.46 (d, J=9.7 Hz, 1H), 4.30 (d, J=9.9 Hz, 1H),4.13 (d, J=13.1 Hz, 2H), 3.99-3.87 (m, 2H), 3.87-3.69 (m, 3H), 3.64 (s,3H), 3.57 (s, 2H), 2.97-2.84 (m, 3H), 2.84-2.73 (m, 1H), 2.34 (s, 2H),1.44 (d, J=16.1 Hz, 1H), 1.29 (s, 2H), 1.26 (s, 2H), 1.14 (d, J=4.9 Hz,6H), 1.10 (s, 3H), 1.02 (s, 3H).

Example 192

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(192). Intermediates: I3, P4 and S7a. MS (ESI) m/z 1078.1 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.65 (s, 3H), 8.14 (d, J=9.1 Hz, 1H), 8.09 (d,J=2.8 Hz, 2H), 7.52 (t, J=59.8 Hz, 2H), 7.43 (dd, J=12.4, 8.0 Hz, 6H),7.31 (d, J=7.8 Hz, 3H), 6.92 (d, J=2.8 Hz, 2H), 6.83 (d, J=9.8 Hz, 1H),4.96 (t, J=7.6 Hz, 3H), 4.46 (d, J=9.6 Hz, 2H), 4.13 (d, J=13.6 Hz, 7H),3.97 (d, J=13.1 Hz, 2H), 3.75 (s, 2H), 3.62 (s, 5H), 3.56 (s, 4H), 3.46(d, J=14.3 Hz, 4H), 2.92 (t, J=8.5 Hz, 2H), 2.81 (d, J=10.7 Hz, 3H),2.21 (d, J=11.4 Hz, 3H), 2.01 (d, J=9.0 Hz, 3H), 1.27 (d, J=13.9 Hz,1H), 1.13 (s, 6H), 1.10 (s, 5H), 0.84 (s, 14H).

Example 193

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(193). Intermediates: I3, P10 and S7a. MS (ESI) m/z 1092.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.65 (s, 2H), 8.14 (d, J=9.2 Hz, 1H), 7.72(d, J=2.4 Hz, 1H), 7.39 (dd, J=17.0, 8.2 Hz, 4H), 7.31 (d, J=7.8 Hz,2H), 6.83 (d, J=9.8 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.21 (tt, J=55.4,3.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.76 (s, 1H), 4.59 (td, J=14.3, 4.0Hz, 2H), 4.49-4.41 (m, 1H), 4.12 (d, J=20.4 Hz, 4H), 3.96 (d, J=13.1 Hz,1H), 3.76 (s, 2H), 3.62 (s, 3H), 3.56 (s, 3H), 3.47 (d, J=14.5 Hz, 2H),2.92 (t, J=8.4 Hz, 2H), 2.80 (d, J=9.5 Hz, 2H), 2.26-2.10 (m, 2H), 2.01(d, J=9.2 Hz, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 0.85 (s, 9H).

Example 194

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(194) Intermediates: I2, P13 and S6a. MS (ESI) m/z 1092.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.87 (d,J=9.0 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.32 (d, J=7.9 Hz, 2H), 7.23 (dd,J=14.4, 8.2 Hz, 4H), 6.76 (d, J=9.4 Hz, 2H), 6.54 (d, J=2.4 Hz, 1H),4.93 (s, 1H), 4.61-4.53 (m, 1H), 4.52-4.46 (m, 1H), 4.45-4.27 (m, 2H),4.21 (d, J=9.9 Hz, 1H), 4.03 (d, J=13.0 Hz, 2H), 3.83 (d, J=13.0 Hz,1H), 3.72 (d, J=9.6 Hz, 1H), 3.66-3.56 (m, 1H), 3.55 (s, 3H), 3.46 (s,3H), 2.82 (d, J=7.2 Hz, 0H), 2.70 (d, J=9.8 Hz, 1H), 2.22 (s, 2H), 1.05(d, J=5.1 Hz, 8H), 0.98 (d, J=16.3 Hz, 3H), 0.92 (s, 2H).

Example 195

methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(195). Intermediates: I2, P10 and S3c. MS (ESI) m/z 1146.1 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.29 (s, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.83(d, J=9.0 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.28(d, J=8.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.02 (d, J=9.8 Hz, 1H), 6.89(d, J=8.9 Hz, 1H), 6.74 (d, J=9.8 Hz, 1H), 6.64 (d, J=2.5 Hz, 1H), 6.12(tt, J=55.3, 3.9 Hz, 1H), 4.86 (t, J=7.6 Hz, 2H), 4.74-4.66 (m, 2H),4.51 (td, J=14.3, 3.9 Hz, 2H), 4.45-4.33 (m, 2H), 4.26-4.09 (m, 3H),4.03 (d, J=8.7 Hz, 4H), 3.84 (d, J=13.2 Hz, 1H), 3.67 (s, 1H), 3.54 (s,3H), 3.46 (s, 2H), 3.32 (s, 1H), 3.29 (d, J=1.7 Hz, 1H), 2.91-2.73 (m,2H), 2.70 (d, J=9.4 Hz, 1H), 2.14 (t, J=6.4 Hz, 2H), 2.01 (d, J=8.5 Hz,2H), 1.05 (d, J=3.7 Hz, 6H), 1.01 (s, 3H), 0.92 (s, 2H).

Example 196

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(196). Intermediates: I2, P4 and S6a. MS (ESI) m/z 1117.2 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.07 (d, J=9.2 Hz, 1H), 8.01(d, J=2.7 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.44 (t, J=59.8 Hz, 1H), 7.34(dd, J=11.9, 8.1 Hz, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.02 (d, J=10.0 Hz,1H), 6.84 (d, J=2.7 Hz, 1H), 6.75 (t, J=10.2 Hz, 1H), 5.01-4.89 (m, 1H),4.59 (dd, J=8.3, 4.8 Hz, 1H), 4.51 (dd, J=8.0, 5.0 Hz, 1H), 4.37 (dd,J=19.9, 10.1 Hz, 3H), 4.20 (d, J=10.0 Hz, 1H), 4.06 (d, J=13.2 Hz, 2H),3.85 (d, J=13.2 Hz, 1H), 3.81-3.61 (m, 2H), 3.56 (d, J=4.6 Hz, 3H),3.53-3.43 (m, 2H), 2.82 (d, J=9.0 Hz, 2H), 2.75-2.61 (m, 1H), 2.22 (s,2H), 1.05 (s, 6H), 1.01 (s, 3H), 0.92 (s,3H).

Example 197

Methyl((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(197). Intermediates: I2, P10 and S7a. MS (ESI) m/z 1146.4 [M+H]¹H NMR(400 MHz, Methanol-d4) δ 8.65 (s, 2H), 8.15 (d, J=9.4 Hz, 1H), 7.73 (d,J=2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (d,J=7.9 Hz, 2H), 7.10 (d, J=9.9 Hz, 1H), 6.84 (d, J=9.7 Hz, 1H), 6.73 (d,J=2.4 Hz, 1H), 6.21 (tt, J=55.3, 4.0 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H),4.84-4.73 (m, 4H), 4.60 (td, J=14.3, 3.9 Hz, 2H), 4.49-4.42 (m, 1H),4.33-4.26 (m, 1H), 4.21-4.08 (m, 4H), 3.94 (d, J=13.2 Hz, 1H), 3.81-3.71(m, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.47 (d, J=14.4 Hz, 2H), 2.99-2.74(m, 4H), 2.28-2.12 (m, 2H), 2.05-1.91 (m, 2H), 1.15 (s, 3H), 1.14 (s,3H), 1.10 (s, 3H), 1.02 (s, 3H). 19F NMR (376 MHz, Methanol-d4) δ-77.37, -77.69, -77.80, -115.42, -125.27 (dt, J=55.2, 14.3 Hz).

Example 198

methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(198). Intermediates: I2, P13 and S7a. MS (ESI) m/z 1122.5 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.56 (s, 2H), 8.07 (d, J=9.3 Hz, 1H), 7.60(d, J=2.4 Hz, 1H), 7.32 (d, J=7.9 Hz, 2H), 7.28-7.16 (m, 4H), 7.03 (d,J=10.0 Hz, 1H), 6.75 (d, J=9.8 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.87 (t,J=7.6 Hz, 2H), 4.76-4.70 (m, 2H), 4.67 (s, 1H), 4.37 (d, J=9.9 Hz, 1H),4.21 (d, J=10.0 Hz, 1H), 4.12-3.99 (m, 4H), 3.84 (d, J=13.2 Hz, 1H),3.66 (s, 1H), 3.60 (tt, J=7.3, 3.9 Hz, 1H), 3.55 (s, 3H), 3.47 (s, 3H),3.38 (d, J=14.3 Hz, 2H), 2.89-2.62 (m, 4H), 2.18-2.06 (m, 2H), 1.96-1.85(m, 2H), 1.12-0.93 (m, 13H), 0.93 (s, 3H).

Example 199

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(199). Intermediates: I2, P4 and S7a. MS (ESI) m/z 1132.9 [M+H]⁺. 1H NMR(400 MHz, Methanol-d4) δ 8.56 (s, 2H), 8.08 (d, J=9.4 Hz, 1H), 8.01 (d,J=2.7 Hz, 1H), 7.44 (t, J=59.9, 59.5 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H),7.33 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.04 (d, J=9.9 Hz, 1H),6.84 (d, J=2.7 Hz, 1H), 6.77 (d, J=9.9 Hz, 1H), 4.87 (t, J=7.6 Hz, 2H),4.72 (dd, J=8.3, 5.0 Hz, 2H), 4.69 (s, 2H), 4.37 (d, J=9.8 Hz, 1H), 4.20(d, J=10.0 Hz, 1H), 4.12-3.96 (m, 4H), 3.85 (d, J=13.1 Hz, 1H), 3.67 (s,1H), 3.55 (s, 3H), 3.47 (s, 3H), 3.37 (d, J=14.3 Hz, 2H), 2.87-2.75 (m,3H), 2.75-2.66 (m, 1H), 1.92 (d, J=9.2 Hz, 2H), 1.05 (s, 6H), 1.01 (s,3H), 0.93 (s, 3H).

Example 200

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridin-2-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(200). Intermediates: I2, P4 and S31b. MS (ESI) m/z 1182.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.22-8.04 (m, 3H), 8.01 (d, J=2.7 Hz, 2H),7.85 (d, J=7.9 Hz, 2H), 7.44 (t, J=59.7 Hz, 1H), 7.41 (d, J=9.5 Hz, 1H),7.36 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H),4.89 (t, J=7.6 Hz, 2H), 4.74 (dd, J=8.2, 5.1 Hz, 2H), 4.53 (d, J=14.1Hz, 2H), 4.37 (s, 1H), 4.21 (s, 1H), 4.16-4.01 (m, 4H), 3.86 (d, J=13.1Hz, 1H), 3.71 (s, 1H), 3.54 (s, 3H), 3.44 (d, J=13.8 Hz, 2H), 3.41-3.33(m, 3H), 2.95-2.63 (m, 5H), 2.22-2.10 (m, 2H), 2.11-1.96 (m, 2H),1.25-1.16 (m, 1H), 1.05 (s, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 201

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(201). Intermediates: I2, P16 and S7a. MS (ESI) m/z 1094.8 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.86 (d, J=4.9 Hz, 1H), 8.65 (s, 1H), 8.14(d, J=9.4 Hz, 0H), 7.96 (d, J=8.6 Hz, 1H), 7.48-7.37 (m, 2H), 7.32 (d,J=7.9 Hz, 1H), 7.08 (d, J=10.0 Hz, 0H), 6.83 (d, J=9.9 Hz, 0H), 4.96 (t,J=7.6 Hz, 1H), 4.83 (s, 8H), 4.53-4.41 (m, 0H), 4.37-4.25 (m, 1H),4.23-4.07 (m, 2H), 3.98 (d, J=13.1 Hz, 1H), 3.78 (s, 0H), 3.65 (s, 2H),3.56 (s, 1H), 3.52-3.39 (m, 1H), 3.00-2.75 (m, 2H), 2.26-2.14 (m, 1H),2.02 (t, J=7.0 Hz, 1H), 1.12 (d, J=13.2 Hz, 5H), 1.02 (s, 1H).

Example 202

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(202a). The title compound 202a was prepared according to the methodpresented for the synthesis of compound 1a but instead utilizing P4. MS(ESI) m/z 1014.4 [M+H]⁺.

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(202)

In a 20 mL vial, a solution of 202a (50 mg, 0.05 mmol), S53 (38.1 mg,0.08 mmol), XPhos Pd G2 (16.4 mg, 0.01 mmol),2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.6 mg, 0.01mmol) and Potassium phosphate tribasic (106 mg, 0.5 mmol) in dioxane (3mL) and water (1 mL) was degassed for 10 min with argon. The mixture washeated to 100° C. for 1 h. The reaction was cooled to room temperature,diluted with MeOH, filtered through Celite, and the filtrate wasconcentrated under vacuum. The residue was purified by HPLC and theproduct was lyophilized to afford 202 MS (ESI) m/z 1117.5 [M+H]^(|). ¹HNMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.11 (d, J=9.3 Hz, 1H), 8.02(d, J=2.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.44 (t, J=59.8 Hz, 1H), 7.35(dd, J=8.1, 3.9 Hz, 4H), 7.22 (d, J=7.9 Hz, 2H), 7.05 (d, J=10.0 Hz,1H), 6.90-6.80 (m, 2H), 6.78 (d, J=9.8 Hz, 0H), 4.88 (t, J=7.3 Hz, 2H),4.52 (dd, J=8.1, 4.3 Hz, 4H), 4.38 (d, J=9.5 Hz, 1H), 4.21 (d, J=9.9 Hz,1H), 4.06 (d, J=12.5 Hz, 4H), 3.87 (t, J=14.4 Hz, 3H), 3.68 (s, 1H),3.55 (s, 3H), 3.46 (s, 2H), 2.94-2.76 (m, 3H), 2.76-2.64 (m, 1H), 2.03(d, J=11.1 Hz, 1H), 1.05 (s, 6H), 1.01 (s, 3H), 0.91 (s, 3H).

Example 203

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(203). Intermediates: I2, P22 and S60. MS (ESI) m/z 1259.4 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H),7.94 (s, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 7.19 (d,J=8.4 Hz, 2H), 6.99 (dd, J=19.7, 9.0 Hz, 2H), 4.95 (dd, J=7.5, 2.8 Hz,4H), 4.85-4.72 (m, 5H), 4.61-4.24 (m, 7H), 4.16 (s, 6H), 3.73-3.44 (m,6H), 3.44-3.34 (m, 3H), 2.99-2.73 (m, 2H), 2.35-2.21 (m, 3H), 1.29 (s,18H), 1.19-0.96 (m, 10H).

Example 204

Methyl((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(204). Intermediates: I2, P13 and S60. MS (ESI) m/z 1121.2 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.19 (s, 0H), 7.69 (d, J=2.5Hz, 1H), 7.53-7.22 (m, 7H), 6.98 (d, J=8.8 Hz, 1H), 6.63 (d, J=2.5 Hz,1H), 4.54 (d, J=59.0 Hz, 0H), 4.38-4.24 (m, 4H), 4.24-3.93 (m, 6H), 3.64(d, J=6.0 Hz, 5H), 3.56-3.39 (m, 6H), 2.09 (d, J=8.5 Hz, 2H), 1.42-0.62(m, 16H).

Example 205

Methyl((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(205). Intermediates: I3, P40 and S60. MS (ESI) m/z 1123.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.39-8.33 (m, 1H), 8.10 (dd, J=19.9, 9.2Hz, 2H), 7.53 (d, J=7.3 Hz, 3H), 7.45 (d, J=7.9 Hz, 3H), 7.32 (d, J=7.9Hz, 3H), 7.13 (dd, J=21.7, 9.5 Hz, 2H), 4.99-4.83 (m, 4H), 4.61-4.50 (m,2H), 4.50-4.43 (m, 1H), 4.35-4.24 (m, 5H), 4.18 (d, J=11.8 Hz, 5H), 3.78(s, 1H), 3.67 (s, 4H), 3.59 (d, J=13.0 Hz, 7H), 3.01-2.76 (m, 5H),2.35-2.23 (m, 4H), 2.14 (t, J=6.9 Hz, 3H), 1.32-1.10 (m, 19H), 1.10-0.95(m, 5H).

Example 206

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(206). Intermediates: I1, P41 and S60. MS (ESI) m/z 987.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.36 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H),7.44 (d, J=7.9 Hz, 2H), 7.36-7.28 (m, 4H), 7.07 (d, J=9.0 Hz, 1H), 6.64(d, J=2.3 Hz, 1H), 4.95 (t, J=7.5 Hz, 2H), 4.83 (dd, J=8.0, 5.1 Hz, 2H),4.53 (dq, J=12.1, 6.2, 5.7 Hz, 1H), 4.28 (dd, J=14.1, 2.4 Hz, 2H),4.19-4.06 (m, 4H), 4.00-3.89 (m, 5H), 3.75 (s, 2H), 3.60 (d, J=16.6 Hz,6H), 3.49 (d, J=13.6 Hz, 2H), 2.95 (td, J=12.3, 11.7, 7.2 Hz, 2H),2.87-2.79 (m, 2H), 2.29-2.21 (m, 2H), 2.20-2.08 (m, 2H), 0.88 (s, 9H),0.82 (s, 9H).

Example 207

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(207). Intermediates: I2, P41 and S60. MS (ESI) m/z 1095.3 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d₄) δ 8.36 (d, J=2.3 Hz, 1H), 8.15 (d, J=9.3 Hz,1H), 7.62 (d, J=2.3 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.33 (dd, J=8.2,5.3 Hz, 4H), 7.12 (dd, J=19.4, 9.5 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 4.95(t, J=7.5 Hz, 2H), 4.85 (dd, J=8.1, 5.1 Hz, 2H), 4.58-4.44 (m, 2H),4.35-4.23 (m, 3H), 4.22-4.09 (m, 4H), 3.93 (s, 4H), 3.65 (s, 3H),3.60-3.52 (m, 4H), 3.01-2.89 (m, 2H), 2.88-2.74 (m, 2H), 2.30-2.23 (m,2H), 2.14 (t, J=6.9 Hz, 2H), 1.18-1.08 (m, 8H), 1.02 (s, 3H).

Example 208

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(208). Intermediates: I2, P4 and S60. MS (ESI) m/z 1131.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.36 (d, J=2.3 Hz, 1H), 8.16-8.02 (m, 2H), 7.44(h, J=4.1, 3.5 Hz, 3H), 7.40-7.29 (m, 2H), 7.14 (d, J=9.1 Hz, 1H), 6.93(d, J=2.7 Hz, 1H), 4.95 (t, J=7.5 Hz, 2H), 4.58-4.43 (m, 2H), 4.34-4.23(m, 3H), 4.21-4.11 (m, 3H), 4.00-3.91 (m, 1H), 3.77 (s, 1H), 3.67-3.52(m, 6H), 3.01-2.86 (m, 3H), 2.80 (dd, J=12.6, 9.1 Hz, 1H), 2.31-2.23 (m,2H), 2.22-2.08 (m, 2H), 1.13 (d, J=14.1 Hz, 7H), 1.03 (s, 2H).

Example 209

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(209). Intermediates: I2, P4and1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.MS (ESI) m/z 1004.5 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.32 (s,2H), 8.09 (d, J=2.7 Hz, 2H), 8.02 (s, 2H), 7.66 (d, J=19.3 Hz, 1H),7.56-7.31 (m, 13H), 7.24 (d, J=8.0 Hz, 5H), 6.91 (d, J=2.7 Hz, 2H), 4.46(s, 2H), 4.31 (s, 2H), 4.20-4.07 (m, 5H), 3.93 (d, J=13.1 Hz, 2H), 3.76(s, 2H), 3.64 (s, 6H), 3.56 (s, 6H), 3.35 (s, 1H), 2.95-2.84 (m, 7H),2.79 (dd, J=12.6, 9.2 Hz, 3H), 1.24-1.09 (m, 28H), 1.02 (s, 6H).

Example 210

Cyclopropyl((S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanamido)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(210). Intermediates: I2a, A4, P7and1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleMS (ESI) m/z 1056.6 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.53 (d,J=0.8 Hz, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.52-7.45 (m,4H), 7.25 (d, J=8.2 Hz, 4H), 4.47 (s, 1H), 4.32 (s, 1H), 4.14 (s, 1H),4.01 (td, J=5.6, 3.0 Hz, 1H), 3.93 (d, J=12.1 Hz, 2H), 3.76 (d, J=8.5Hz, 1H), 2.94-2.73 (m, 5H), 2.01 (s, 2H), 1.23 (t, J=7.1 Hz, 2H),1.17-1.09 (m, 10H), 1.02 (s, 3H), 0.69-0.51 (m, 8H).

Example 211

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(211). Intermediates: I2, P7and1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleMS (ESI) m/z 1004.2 [M+H]^(|). ¹H NMR (400 MHz, Methanol-d₄) δ 8.44 (d,J=0.7 Hz, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.41 (s, 1H),7.39-7.35 (m, 3H), 7.25 (d, J=10.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 4H), 4.35(s, 1H), 4.20 (s, 1H), 4.05-3.98 (m, 3H), 3.85 (s, 1H), 3.54 (s, 4H),3.46 (s, 3H), 2.82-2.65 (m, 4H), 1.91 (s, 1H), 1.08-0.99 (m, 9H), 0.92(s, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ -76.33-79.41 (m), -96.67 (dd,J=145.1, 59.7 Hz).

Example 212

Synthesis of methyl((5S,10S,11S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate(212a). The title compound 212a was prepared according to the methodpresented for the synthesis of compound 188 but instead utilizing I2 andP10a. MS (ESI) m/z 776.3 [M+H]⁺.

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(212) The title compound 212 was prepared according to the methodpresented for the synthesis of compound 1a but instead utilizing 212aand P20. MS (ESI) m/z 1146.3 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.71 (s, 2H), 8.11 (d, J=9.7 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.64 (d,J=7.9 Hz, 2H), 7.25 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.13 (d, J=10.1 Hz,1H), 6.78 (d, J=10.1 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.19 (tt, J=55.6,3.9 Hz, 1H), 4.96 (t, J=7.5 Hz, 2H), 4.56 (td, J=14.3, 3.9 Hz, 2H), 4.43(d, J=9.7 Hz, 1H), 4.29 (d, J=10.0 Hz, 1H), 4.23-4.08 (m, 4H), 3.95 (d,J=13.5 Hz, 1H), 3.73 (s, 1H), 3.63 (s, 3H), 3.55 (s, 3H), 3.52-3.43 (m,2H), 2.93-2.73 (m, 3H), 2.25-2.17 (m, 2H), 2.06-1.94 (m, 2H), 1.15-1.12(m, 6H), 1.11 (s, 3H), 1.01 (s, 3H).

Example 213

Synthesis of tert-butyl((6S,9S,10S,15S)-12-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17-trifluoro-10-hydroxy-9-(4-iodobenzyl)-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,12,13-tetraazaheptadecan-15-yl)carbamate(213a). The title compound 213a was prepared according to the methodpresented for the synthesis of compound 188 but instead utilizing I2a,A1, and P4.

Synthesis of tert-butyl((6S,9S,10S,15S)-12-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-17,17,17-trifluoro-10-hydroxy-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,12,13-tetraazaheptadecan-15-yl)carbamate(213b). The title compound 213b was prepared according to the methodpresented for the synthesis of compound 218 but instead utilizing 213aand1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.MS (ESI) m/z 1088.5 [M+H]⁺.

Synthesis ofN-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)cyclopropanecarboxamide(213). To a solution of 213a (255 mg, 0.23 mmol) in CH₂Cl₂ (5 mL) atroom temperature was added 4 M hydrochloric acid (0.8 mL). Afterstirring for 18h the reaction and the mixture was concentrated in vacuo.To this crude residue dissolved in DMF (3 mL) was addedcyclopropanecarboxylic acid (29.97 μl, 0.4 mmol), HATU (93.32 mg, 0.4mmol) and DIPEA (0.34 ml, 1.96 mmol). The mixture was stirred for 48hthen purified by HPLC HPLC and Lyophilized to give 212. MS (ESI) m/z1146.3 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J=0.7 Hz, 1H),8.25 (d, J=9.8 Hz, 1H), 8.20-8.06 (m, 2H), 8.06-7.95 (m, 2H), 7.56-7.45(m, 4H), 7.48-7.31 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 6.93 (dd, J=5.4, 2.7Hz, 1H), 4.73-4.61 (m, 1H), 4.16 (d, J=13.2 Hz, 2H), 3.93 (d, J=13.2 Hz,1H), 3.77 (s, 1H), 2.93-2.74 (m, 4H), 1.69 (dd, J=8.5, 4.1 Hz, 1H), 1.58(tt, J=8.2, 4.6 Hz, 1H), 1.36-1.20 (m, 1H), 1.17 (d, J=13.5 Hz, 9H),1.07 (s, 3H), 0.91 (q, J=10.2, 9.5 Hz, 1H), 0.89-0.66 (m, 1H), 0.65-0.54(m, 1H).

Example 214

N-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)cyclopropanecarboxamide(214). The title compound 214 was prepared according to the methodpresented for the synthesis of compound 213 but instead utilizing P7. MS(ESI) m/z 1024.5 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.53 (s, 1H),8.33 (d, J=0.7 Hz, 1H), 8.27 (d, J=9.8 Hz, 1H), 8.13-8.09 (m, 2H),8.03-7.96 (m, 2H), 7.64 (d, J=10.5 Hz, 1H), 7.52-7.45 (m, 3H), 7.34 (d,J=10.7 Hz, 1H), 7.24 (t, J=8.5 Hz, 4H), 4.81-4.78 (m, 1H), 4.69-4.64 (m,1H), 4.12 (d, J=12.4 Hz, 2H), 3.91 (d, J=13.2 Hz, 1H), 3.74 (d, J=8.9Hz, 1H), 2.88 (d, J=7.6 Hz, 3H), 2.77 (dd, J=12.5, 9.3 Hz, 1H), 1.69(dt, J=8.0, 3.7 Hz, 1H), 1.57 (tt, J=8.3, 4.6 Hz, 1H), 1.29 (d, J=0.6Hz, 1H), 1.24 (d, J=7.7 Hz, 1H), 1.21-1.12 (m, 9H), 1.06 (s, 2H),0.94-0.68 (m, 7H), 0.59 (d, J=8.0 Hz, 1H).

Example 215

(S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-hydroxybutan-2-yl)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanamide(215). The title compound 215 was prepared according to the methodpresented for the synthesis of compound 213 but instead utilizing P7 andpropionic acid. MS (ESI) m/z 1000.5 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d₄) δ 8.54 (d, J=0.7 Hz, 1H), 8.35 (d, J=0.7 Hz, 1H), 8.14-8.00(m, 5H), 7.71 (d, J=9.8 Hz, 1H), 7.64 (d, J=10.9 Hz, 1H), 7.52-7.44 (m,4H), 7.25 (t, J=8.6 Hz, 5H), 4.78-4.74 (m, 1H), 4.67-4.63 (m, 1H), 4.14(d, J=13.2 Hz, 2H), 3.92 (d, J=13.2 Hz, 1H), 3.73 (d, J=8.7 Hz, 1H),2.88 (d, J=8.7 Hz, 4H), 2.76 (dd, J=12.7, 9.3 Hz, 1H), 2.25-1.99 (m,6H), 1.25-0.95 (m, 24H).

Example 216

N-((S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((2S,3S)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(1-methylcyclopropane-1-carboxamido)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)-1-methylcyclopropane-1-carboxamide(216). The title compound 216 was prepared according to the methodpresented for the synthesis of compound 213 but instead utilizing P7 and1-Methylcyclopropanecarboxylic acid. MS (ESI) m/z 1052.7 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d₄) δ 8.17 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=9.5 Hz,1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.15-7.07 (m, 4H), 6.87 (t, J=8.2 Hz,4H), 6.42 (d, J=9.6 Hz, 1H), 6.17 (d, J=9.6 Hz, 1H), 4.38 (d, J=9.5 Hz,1H), 4.27 (d, J=9.5 Hz, 1H), 3.89-3.73 (m, 2H), 3.58-3.48 (m, 1H), 3.39(s, 1H), 2.50 (t, J=7.6 Hz, 3H), 2.41 (dd, J=12.6, 9.0 Hz, 1H),0.95-0.54 (m, 25H), 0.22 (d, J=3.8 Hz, 2H), 0.13 (ddd, J=9.8, 6.4, 3.6Hz, 1H).

Example 217

(S)-2-acetamido-N-((2S,3S)-4-(2-((S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-hydroxybutan-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide(217). The title compound 217 was prepared according to the methodpresented for the synthesis of compound 213 but instead utilizing P7 andAcetic anhydride. MS (ESI) m/z 972.5 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d₄) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.16 (d, J=21.4 Hz, 2H), 8.07(d, J=20.2 Hz, 2H), 7.52-7.46 (m, 3H), 7.25 (t, J=8.3 Hz, 4H), 5.48 (d,J=0.6 Hz, 2H), 4.78-4.73 (m, 1H), 4.66-4.61 (m, 1H), 4.16 (s, 1H),3.95-3.88 (m, 1H), 3.74 (d, J=8.5 Hz, 1H), 2.91-2.84 (m, 3H), 2.77 (dd,J=12.7, 9.2 Hz, 1H), 2.15 (s, 1H), 2.03 (d, J=0.5 Hz, 15H), 1.93 (s,2H), 1.81 (s, 2H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ -76.14— -79.22 (m),-96.72 (dd, J=133.4, 59.8 Hz).

Example 218

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(218). To a solution of methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(0.02 g, 0.02 mmol) in 1,4-dioxane (0.3 mL) was added1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.01 g, 0.04 mmol), XPhos Pd G2 (0.005 g, 0.003 mmol), XPhos (0.001 g,0.003 mmol) and Potassium phosphate tribasic (0.01 ml) as an aqueoussolution in water (0.01 mL). The resulting suspension was sparged withargon for 5 minutes and subsequently placed in a 100° C. aluminumheating block and let stir, heating, overnight under an atmosphere ofargon. Upon completion, the residue was purified by reverse phase highpressure liquid chromatography (20-83% acetonitrile in water, 0.1% TFAbuffer). The collected product fractions were quenched with sodiumbicarbonate (aqueous, saturated), extracted with ethyl acetate andfurther purified by normal phase silica gel chromatography (0-8%methanol in dichloromethane) to give methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.ES/MS m/z 950.542 [M+H]⁺.

Example 219

Methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(219). Intermediates: P44, A3, and S7. MS (ESI) m/z 1157.9 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.97 (s, 1H), 8.53 (s, 2H), 8.17 (d, J=9.8Hz, 1H), 8.00 (t, J=58.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.35 (d, J=7.9Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.14 (d, J=9.9 Hz, 1H), 6.81 (d, J=9.9Hz, 1H), 4.96 (dd, J=8.2, 7.1 Hz, 2H), 4.83-4.78 (m, 3H), 4.50-4.41 (m,1H), 4.30 (d, J=10.0 Hz, 1H), 4.21-4.08 (m, 4H), 3.96 (d, J=13.2 Hz,1H), 3.74 (d, J=8.8 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.47 (d, J=14.5Hz, 2H), 2.98-2.84 (m, 3H), 2.82-2.74 (m, 1H), 2.29-2.17 (m, 2H),2.02-1.94 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s,3H). 19F NMR (377 MHz, Methanol-d4) δ -77.37, -77.70, -77.82, -98.78 (d,J=58.6 Hz), -114.26.

Example 220

Oxetan-3-yl((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((2S,3S)-2-hydroxy-4-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)phenyl)-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(220). Intermediates: P4, A4, and S7. MS (ESI) m/z 1240.3 [M+H]+. 1H NMR(400 MHz, Methanol-d4) δ 8.45 (s, 2H), 8.12 (d, J=9.3 Hz, 1H), 8.02 (d,J=2.7 Hz, 1H), 7.45 (t, J=59.8 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.25 (d,J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 3H), 7.07 (d, J=10.0 Hz, 1H), 6.85 (d,J=2.8 Hz, 1H), 5.37-5.21 (m, 2H), 4.92-4.83 (m, 2H), 4.73-4.69 (m, 2H),4.56 (ddd, J=12.4, 7.3, 5.2 Hz, 2H), 4.50-4.44 (m, 2H), 4.33 (d, J=10.0Hz, 1H), 4.20 (d, J=9.9 Hz, 1H), 4.13-3.98 (m, 4H), 3.85 (d, J=13.1 Hz,1H), 3.67 (s, 1H), 3.39-3.32 (m, 3H), 2.86-2.78 (m, 3H), 2.68 (dd,J=12.6, 8.9 Hz, 1H), 2.14-2.08 (m, 2H), 1.92-1.83 (m, 2H), 1.09 (s, 3H),1.07 (s, 3H), 1.05-0.99 (m, 3H), 0.99-0.93 (m, 3H). 19F NMR (377 MHz,Methanol-d4) δ -77.46, -77.56, -77.78, -96.92 (d, J=59.7 Hz), -114.94.

Example 221

Methyl((2S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)pethynyl)phenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(221). Intermediate 19 was acylated with cyclopropyl carbonyl chloridein the presence of aqueous 2M NaOH, followed by coupling with S7analgously to the procedure provided for example 1. MS (ESI) m/z 1166.9[M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.42 (s, 2H), 8.07 (d, J=9.4 Hz,1H), 8.01 (d, J=2.7 Hz, 1H), 7.89 (d, J=9.7 Hz, 1H), 7.44 (t, J=59.7 Hz,1H), 7.36 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz,2H), 7.06 (d, J=9.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 4.90-4.83 (m, 2H),4.74-4.68 (m, 3H), 4.21 (d, J=10.0 Hz, 1H), 4.11-3.98 (m, 4H), 3.85 (d,J=13.0 Hz, 1H), 3.57 (s, 3H), 3.41-3.31 (m, 2H), 2.86-2.75 (m, 3H),2.73-2.61 (m, 1H), 2.19-2.01 (m, 2H), 1.93-1.82 (m, 2H), 1.64-1.51 (m,1H), 1.10 (s, 3H), 1.07 (s, 3H), 1.07 (s, 3H), 0.94 (s, 3H), 0.90-0.83(m, 1H), 0.79-0.62 (m, 2H). 19F NMR (377 MHz, Methanol-d4) δ -77.41,-77.71, -77.73, -96.95 (dd, J=59.9, 20.5 Hz), -114.88.

Example 222

Methyl((5S,8S,11S,12S,17S)-8-(tert-butyl)-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-12-hydroxy-5-isopropyl-18,18-dimethyl-11-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,9,16-tetraoxo-2-oxa-4,7,10,14,15-pentaazanonadecan-17-yl)carbamate(222). MS (ESI) m/z 1147.4 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.50(s, 2H), 7.87 (d, J=9.2 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.50 (d, J=9.4Hz, 1H), 7.35-7.24 (m, 4H), 7.16 (d, J=8.0 Hz, 2H), 6.65 (d, J=2.5 Hz,1H), 6.13 (tt, J=55.3, 3.9 Hz, 1H), 4.58-4.44 (m, 4H), 4.39 (s, 0H),4.16 (d, J=9.2 Hz, 1H), 4.07-3.92 (m, 2H), 3.90-3.77 (m, 2H), 3.67 (s,1H), 3.59 (s, 1H), 3.55 (s, 3H), 3.55 (s, 3H), 2.90-2.66 (m, 3H),2.06-1.86 (m, 2H), 0.85 (s, 9H), 0.79 (d, J=6.8 Hz, 3H), 0.76 (s, 9H),0.72 (d, J=6.8 Hz, 3H). 19F NMR (377 MHz, Methanol-d4) δ -77.64,-115.17, -125.29 (dt, J=55.2, 14.2 Hz).

Example 223

Methyl((5S,8S,11S,12S,17S)-5,8-di-tert-butyl-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-12-hydroxy-18,18-dimethyl-11-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,9,16-tetraoxo-2-oxa-4,7,10,14,15-pentaazanonadecan-17-yl)carbamate(223). MS (ESI) m/z 1174.4 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.21(d, J=2.3 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.61(dd, J=8.8, 2.3 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H),7.24 (d, J=8.1 Hz, 1H), 7.15 (d, J=8.1 Hz, 2H), 6.77 (d, J=8.9 Hz, 1H),6.65 (d, J=2.4 Hz, 1H), 6.13 (tt, J=55.3, 3.9 Hz, 1H), 4.92-4.83 (m,2H), 4.74-4.68 (m, 2H), 4.51 (td, J=14.3, 3.9 Hz, 2H), 4.26 (d, J=13.7Hz, 2H), 4.16 (d, J=9.3 Hz, 1H), 4.09-3.94 (m, 3H), 3.91 (s, 1H), 3.85(d, J=13.1 Hz, 1H), 3.70-3.64 (m, 1H), 3.63-3.57 (m, 2H), 3.55 (s, 3H),3.54 (s, 3H), 3.28 (d, J=13.9 Hz, 2H), 2.89-2.66 (m, 4H), 2.17-2.08 (m,2H), 2.02-1.95 (m, 2H), 0.85 (s, 9H), 0.80 (s, 9H), 0.75 (s, 9H). 19FNMR (377 MHz, Methanol-d4) δ -77.71, -115.18, -125.29 (dt, J=55.3, 14.2Hz).

Example 224

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(224). Intermediates: P28, I3, and S25. MS (ESI) m/z 1104.4 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.58 (d, J=5.0 Hz, 1H), 8.14-8.01 (m, 2H),7.93 (t, J=7.7 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.72 (t, J=8.7 Hz, 1H),7.50 (d, J=8.5 Hz, 2H), 7.43-7.35 (m, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.14(d, J=8.0 Hz, 2H), 6.72 (d, J=9.8 Hz, 1H), 4.63-4.54 (m, 1H), 4.39-4.29(m, 1H), 4.11-3.73 (m, 8H), 3.66 (s, 1H), 3.59 (s, 3H), 3.53 (s, 3H),3.13 (d, J=12.1 Hz, 1H), 2.90-2.64 (m, 4H), 2.20-1.67 (m, 10H), 1.05 (s,4H), 1.02 (s, 3H), 0.76 (s, 9H). 19F NMR (377 MHz, Methanol-d4) δ-77.33, -78.06, -114.28

Example 225

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(225). Intermediates: P28, I1, and S25. MS (ESI) m/z 1050.4 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.67 (dt, J=4.9, 1.4 Hz, 1H), 8.19 (d,J=2.8 Hz, 1H), 8.00 (t, J=7.7 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.89-7.74(m, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.48 (t, J=6.2 Hz, 1H), 7.35 (d, J=7.9Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.08-6.89 (m, 1H), 4.73-4.64 (m, 1H),4.23-3.81 (m, 8H), 3.75 (s, 1H), 3.73-3.69 (m, 1H), 3.68 (s, 3H), 3.63(s, 3H), 3.24-3.14 (m, 1H), 2.99-2.79 (m, 4H), 2.32-1.75 (m, 9H), 0.90(s, 9H), 0.84 (s, 9H). 19F NMR (377 MHz, Methanol-d4) δ -78.01, -114.33.

Example 226

methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(226). Intermediates: I1, P41 and S61. MS (ESI) m/z 1033.4 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.31 (d, J=4.9 Hz, 2H), 8.07 (d, J=2.1 Hz,1H), 7.76 (d, J=9.3 Hz, 1H), 7.68 (d, J=9.1 Hz, 1H), 7.52 (d, J=2.3 Hz,1H), 7.29-7.19 (m, 4H), 7.14 (d, J=8.1 Hz, 2H), 6.90 (d, J=9.3 Hz, 1H),6.61 (t, J=4.9 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.92-4.84 (m, 2H),4.08-3.97 (m, 2H), 3.89 (d, J=13.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 1H),3.66 (s, 1H), 3.64-3.59 (m, 1H), 3.58 (s, 3H), 3.56 (s, 3H), 2.87-2.62(m, 3H), 2.06-1.95 (m, 2H), 1.84 (q, J=7.2, 6.6 Hz, 2H), 0.79 (s, 9H),0.74 (s, 9H). 19F NMR (377 MHz, Methanol-d4) δ -77.75, -115.32.

Example 227

Methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(227). Intermediates: I1, P41 and S25. MS (ESI) m/z 1053.3 [M+H]+. 1HNMR (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.79-7.64 (m, 2H), 7.52 (d,J=2.3 Hz, 1H), 7.28-7.19 (m, 4H), 7.14 (d, J=8.0 Hz, 2H), 6.89 (t,J=10.6 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.63-4.55 (m, 1H), 4.09-3.89 (m,3H), 3.84 (s, 3H), 3.81-3.73 (m, 2H), 3.66 (s, 1H), 3.64-3.60 (m, 1H),3.58 (s, 3H), 3.56 (s, 3H), 3.10 (d, J=12.2 Hz, 1H), 2.90-2.61 (m, 4H),2.18-1.67 (m, 7H), 0.80 (s, 9H), 0.75 (s, 9H). 19F NMR (377 MHz,Methanol-d4) δ -77.94, -115.33.

Example 228

Methyl((5S,8S,9S,14S)-8-(4-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(228). Intermediates: I1, and P41. MS (ESI) m/z 971.3 [M+H]+. 1H NMR(400 MHz, Methanol-d4) δ 8.12 (dd, J=2.2, 0.7 Hz, 1H), 7.73 (d, J=9.4Hz, 1H), 7.65 (dd, J=9.0, 2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.32-7.18(m, 4H), 7.14 (d, J=8.1 Hz, 2H), 6.88 (d, J=9.2 Hz, 1H), 4.10-3.97 (m,2H), 3.90-3.76 (m, 5H), 3.70-3.50 (m, 15H), 2.90-2.78 (m, 2H), 2.72 (d,J=7.9 Hz, 2H), 2.06 (s, 3H), 0.80 (s, 9H), 0.75 (s, 9H). 19F NMR (377MHz, Methanol-d4) δ -77.88, -115.32.

Example 229

Methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate($$$). Intermediates: I2, P39, S3. MS (ESI) m/z 1030.2 [M+H]^(|). ¹H NMR(400 MHz, Methanol-d₄) δ 8.55 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.13 (d,J=9.4 Hz, 1H), 8.01-7.87 (m, 2H), 7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.55 (d,J=8.4 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.12 (d,J=9.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 6.79 (d, J=9.9 Hz, 1H), 4.95 (t,J=7.6 Hz, 2H), 4.85-4.78 (m, 2H), 4.58-4.49 (m, 1H), 4.48-4.40 (m, 1H),4.40-4.26 (m, 3H), 4.23-4.09 (m, 4H), 3.98 (d, J=13.1 Hz, 1H), 3.79-3.71(m, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.46-3.35 (m, 2H), 2.94-2.87 (m,3H), 2.80 (t, J=10.9 Hz, 1H), 2.45 (s, 3H), 2.30-2.19 (m, 2H), 2.12-2.00(m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).

Example 230

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I3, P8, and S3. MS (ESI) m/z 1083.8 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.11 (d, J=21.6 Hz, 4H), 7.72-7.55 (m, 3H),7.42-7.29 (m, 5H), 7.22 (d, J=8.1 Hz, 2H), 6.88-6.77 (m, 1H), 4.96 (t,J=7.6 Hz, 2H), 4.81 (dd, J=8.2, 5.0 Hz, 2H), 4.54 (s, 1H), 4.42-4.32 (m,3H), 4.16 (s, 3H), 4.08-3.91 (m, 2H), 3.81-3.60 (m, 9H), 3.42-3.34 (m,2H), 2.98-2.70 (m, 4H), 2.27-2.20 (m, 2H), 2.11-2.03 (m, 2H), 1.08 (d,J=22.3 Hz, 6H), 0.80 (s, 10H).

Example 231

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1a, A7, P8, and S3. MS (ESI) m/z 1083.8 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.48-8.06 (m, 3H), 7.70 (dd, J=8.9, 2.3 Hz,2H), 7.66-7.55 (m, 1H), 7.43-7.30 (m, 5H), 7.24 (d, J=8.1 Hz, 3H), 4.96(t, J=7.6 Hz, 2H), 4.82 (dd, J=8.3, 5.1 Hz, 3H), 4.54 (s, 1H), 4.35 (d,J=13.4 Hz, 2H), 4.24-3.89 (m, 12H), 3.83-3.59 (m, 8H), 3.39 (d, J=13.8Hz, 2H), 3.00-2.72 (m, 4H), 2.28-2.19 (m, 2H), 2.12-2.00 (m, 2H),0.92-0.75 (m, 13H).

Example 232

methyl((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1, P4, and S3. MS (ESI) m/z 1047.5 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.30-8.26 (m, 1H), 8.09 (d, J=2.7 Hz, 1H), 7.80 (d,J=9.4 Hz, 1H), 7.68 (dd, J=9.0, 2.5 Hz, 2H), 7.48-7.31 (m, 5H), 7.23 (d,J=8.0 Hz, 2H), 6.93 (d, J=2.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 4.94 (t,J=7.5 Hz, 2H), 4.46 (s, 1H), 4.30 (d, J=13.8 Hz, 2H), 4.18-4.02 (m, 5H),4.02-3.88 (m, 3H), 3.79-3.63 (m, 9H), 3.35 (d, J=13.7 Hz, 2H), 2.98-2.77(m, 5H), 2.24-2.16 (m, 2H), 2.04 (d, J=8.4 Hz, 2H), 0.87 (d, J=21.8 Hz,19H).

Example 233

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1a, A7, P7, and S3. MS (ESI) m/z 1084.0 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.31-8.28 (m, 1H), 8.12 (s, 1H), 7.88 (d, J=9.4Hz, 1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.37-7.21 (m, 7H), 6.86 (d, J=8.9Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.81 (dd, J=8.0, 5.2 Hz, 3H), 4.52 (s,1H), 4.35 (d, J=14.0 Hz, 2H), 4.25-3.89 (m, 13H), 3.67 (d, J=8.3 Hz,8H), 3.37 (d, J=13.8 Hz, 2H), 2.95-2.78 (m, 4H), 2.26-2.19 (m, 2H), 2.07(d, J=8.6 Hz, 2H), 0.95-0.83 (m, 13H).

Example 234

methyl((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1a, A7, P26, and S3. MS (ESI) m/z 1060.3 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.65 (d, J=4.8 Hz, 1H), 8.31-8.28 (m, 1H), 7.91(q, J=13.2, 11.5 Hz, 4H), 7.73-7.65 (m, 2H), 7.34 (d, J=7.9 Hz, 2H),7.24 (d, J=8.0 Hz, 2H), 4.96 (t, J=7.6 Hz, 2H), 4.81 (dd, J=8.3, 5.0 Hz,3H), 4.52 (s, 1H), 4.35 (d, J=14.1 Hz, 2H), 4.30-3.96 (m, 12H), 3.73 (s,1H), 3.66 (d, J=16.2 Hz, 6H), 3.38 (d, J=13.8 Hz, 2H), 2.99-2.78 (m,5H), 2.23 (d, J=10.7 Hz, 2H), 2.07 (d, J=8.7 Hz, 2H), 0.93-0.81 (m,13H).

Example 235

methyl((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I2, P14, and S3. MS (ESI) m/z 1116.4 [M+H]⁺.

Example 236

methyl((5S,8S,9S,14S)-8-(4-((6-(8-(2,2-difluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: P4, A3, and S63. MS (ESI) m/z 1078.4 [M+H]+. ¹H NMR (400MHz, Methanol-d4) δ 8.29-8.24 (m, 1H), 8.18-8.08 (m, 2H), 7.74-7.61 (m,3H), 7.59-7.51 (m, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.39-7.31 (m, 2H), 7.22(d, J=8.0 Hz, 2H), 6.93 (d, J=2.7 Hz, 1H), 6.88 (d, J=8.9 Hz, 1H),4.33-4.28 (m, 1H), 4.27-4.10 (m, 7H), 3.95 (d, J=13.2 Hz, 1H), 3.68 (d,J=10.7 Hz, 10H), 3.42 (d, J=13.5 Hz, 2H), 2.95-2.73 (m, 4H), 2.29 (d,J=10.5 Hz, 2H), 2.08 (d, J=8.6 Hz, 2H), 1.20-1.08 (m, 10H), 1.03 (s,3H).

Example 237

methyl((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I3, P26, and S3. MS (ESI) m/z 1060.3 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.65 (d, J=4.8 Hz, 1H), 8.12 (d, J=9.4 Hz, 1H), 7.92(dd, J=18.0, 8.2 Hz, 3H), 7.73-7.65 (m, 2H), 7.42 (t, J=5.5 Hz, 1H),7.33 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.9 Hz, 1H),4.96 (t, J=7.6 Hz, 2H), 4.81-4.76 (m, 3H), 4.46-4.23 (m, 5H), 4.18-4.03(m, 5H), 3.68 (s, 5H), 3.62 (s, 3H), 3.37 (d, J=14.0 Hz, 3H), 2.96-2.75(m, 4H), 2.23 (d, J=10.2 Hz, 2H), 2.08 (d, J=8.7 Hz, 2H), 1.12 (d,J=16.0 Hz, 7H), 0.84 (s, 10H).

Example 238

methyl((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-8-(4-((6-(8-(2,2-difluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1a, A7, P26, and S63. MS (ESI) m/z 1068.6 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.65 (d, J=4.9 Hz, 1H), 8.28-8.24 (m, 1H),8.00-7.82 (m, 4H), 7.75-7.65 (m, 2H), 7.47-7.41 (m, 1H), 7.34 (d, J=7.9Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.9 Hz, 1H), 4.31-3.95 (m,15H), 3.66 (d, J=15.6 Hz, 10H), 3.43 (d, J=13.4 Hz, 2H), 2.99-2.79 (m,4H), 2.34-2.24 (m, 2H), 2.08 (t, J=7.0 Hz, 2H), 0.96-0.80 (m, 14H).

Example 239

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I2, P15, and S3. MS (ESI) m/z 1134.4 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.65 (dd, J=8.6, 5.6 Hz, 1H), 8.29 (d, J=2.2 Hz,1H), 8.12 (d, J=9.5 Hz, 1H), 7.78-7.61 (m, 5H), 7.33 (d, J=7.8 Hz, 2H),7.25-7.18 (m, 3H), 6.85 (d, J=8.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.53(s, 1H), 4.44 (d, J=9.7 Hz, 1H), 4.33 (dd, J=19.5, 12.0 Hz, 4H), 4.17(d, J=14.3 Hz, 5H), 3.98 (d, J=13.1 Hz, 1H), 3.67 (d, J=16.2 Hz, 8H),3.38 (d, J=13.8 Hz, 2H), 2.96-2.75 (m, 5H), 2.23 (d, J=11.2 Hz, 2H),2.08 (d, J=8.6 Hz, 2H), 1.18-1.10 (m, 10H), 1.03 (s, 3H).

Example 240

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-((6-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)pethynyl)benzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I2, P28, and S22. MS (ESI) m/z 1102.1 [M+H]⁺.

Example 241

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-8-(4-((6-(8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I2, P28, and S21. MS (ESI) m/z 1088.1 [M+H]⁺.

Example 242

methyl((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I2, P28, and S20. MS (ESI) m/z 1074.4 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.65 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J=8.1Hz, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.33 (d, J=7.9Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.9 Hz, 1H), 4.44 (d, J=9.7Hz, 1H), 4.33 (dd, J=19.0, 11.6 Hz, 3H), 4.20-4.06 (m, 5H), 3.98 (d,J=13.0 Hz, 1H), 3.66 (d, J=21.3 Hz, 8H), 3.26 (s, 1H), 2.91 (d, J=7.9Hz, 7H), 2.31 (s, 2H), 2.07 (d, J=8.8 Hz, 2H), 1.19-1.10 (m, 11H), 1.03(s, 3H).

Example 243

methyl((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I3, P9, and S3. MS (ESI) m/z 1065.6 [M+H]⁺. ¹H NMR (400MHz, Methanol-d4) δ 8.39-8.28 (m, 2H), 8.08 (d, J=26.3 Hz, 2H), 7.70(dd, J=8.8, 2.3 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.43 (d,J=8.1 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.88-6.73(m, 2H), 4.96 (t, J=7.6 Hz, 2H), 4.81 (dd, J=8.2, 5.0 Hz, 2H), 4.52 (s,1H), 4.37 (t, J=13.2 Hz, 3H), 4.15 (s, 3H), 3.95 (t, J=10.7 Hz, 2H),3.78 (d, J=9.5 Hz, 1H), 3.69 (d, J=10.5 Hz, 5H), 3.62 (s, 3H), 3.38 (d,J=13.9 Hz, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.79 (t, J=11.1 Hz, 2H), 2.23(d, J=11.0 Hz, 2H), 2.07 (d, J=8.6 Hz, 2H), 1.09 (s, 3H), 1.01 (s, 3H),0.76 (s, 10H).

Example 244

methyl((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.Intermediates: I1a, A7, P26, and S62. MS (ESI) m/z 1086.4 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 8.67-8.62 (m, 1H), 7.99-7.80 (m, 5H), 7.71-7.61(m, 2H), 7.59-7.51 (m, 1H), 7.44 (dd, J=7.1, 5.1 Hz, 1H), 7.36 (d, J=7.9Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.30-3.96 (m, 10H), 3.90 (d, J=9.1 Hz,1H), 3.84 (d, J=11.5 Hz, 2H), 3.77-3.46 (m, 10H), 3.23-3.11 (m, 3H),2.99-2.80 (m, 5H), 2.08-1.98 (m, 3H), 1.78 (t, J=7.1 Hz, 2H), 0.95-0.80(m, 12H).

Example 245

Methyl((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate(ABC). Intermediates: I2, P29, and S3. MS (ESI) m/z 1098.7 [M+H]⁺. ¹HNMR (400 MHz, Methanol-d4) δ 8.65-8.61 (m, 1H), 8.29 (d, J=2.3 Hz, 1H),8.11 (d, J=9.1 Hz, 1H), 7.92 (dd, J=18.5, 7.8 Hz, 2H), 7.75-7.62 (m,4H), 7.33 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.15 (d, J=9.9 Hz,1H), 6.85 (d, J=8.9 Hz, 1H), 4.96 (t, J=7.6 Hz, 3H), 4.82-4.76 (m, 2H),4.53-4.12 (m, 10H), 3.99 (d, J=13.7 Hz, 3H), 3.76 (s, 1H), 3.68 (s, 3H),3.58 (s, 3H), 3.37 (d, J=14.0 Hz, 2H), 2.86 (dd, J=31.3, 7.8 Hz, 4H),2.22 (d, J=10.8 Hz, 2H), 2.07 (d, J=8.8 Hz, 2H), 1.18-1.05 (m, 9H), 0.94(s, 3H).

4. Biological Assays

MT-4 HIV Assay

Compounds were tested in a high-throughput 384-well assay format fortheir ability to inhibit the replication of HIV-1 (IIIB) in MT-4 cells.Compounds were serially diluted (1:3) in DMSO on 384-well polypropyleneplates and further diluted 200-fold into complete RPMI media (10% FBS,1% P/S) using the Biotek Micro Flow and Agilent ECHO acoustic dispenser.Each plate contained up to 8 test compounds, with negative (No DrugControl) and 5 uM AZT positive controls. MT-4 cells were pre-infectedwith 10 uL of either RPMI (mock-infected) or a fresh 1:250 dilution ofan HIV-1 (IIIB) concentrated virus stock. Infected and uninfected MT-4cells were further diluted in complete RPMI media and added to eachplate using a Micro Flow dispenser. After 5 days incubation in ahumidified and temperature controlled incubator (37° C.), Cell Titer Glo(Promega) was added to the assay plates to quantify the amount ofluciferase. EC₅₀ and CC₅₀ values were defined as the compoundconcentration that causes a 50% decrease in luminescence signal, andwere calculated using a sigmoidal dose-response model to generate curvefits. Data for certain compounds is reported in Table 1 below.

MT-4 HIV High Resolution Antiviral Assay

Assay protocol is identical to that described for the MT-4 antiviralassay with the following changes: Each drug is run in 2 series ofquadruplicates with different starting concentrations for each seriesand 19 1.5 fold dilutions performed across the plate. This results in aninhibition curve with 40 data points for each compound. Data is analyzedand Hill coefficients determined in Graph Pad Prism (San Diego, Calif.).EC₉₅s were determined by the formula EC₉₅=(19)^(1/hill coefficient)×HDvalues were determined for certain compounds and reported in Table 5below as an illustrative example.

Liver Microsomal Stability Protocol

Test compounds and one control compound (verapamil) were tested in 3different species in duplicate sets.

General Conditions:

Test compound concentration: 1 uM; Protein concentration: 0.5 mg/mL (fordog, rat, and human liver microsomes); Cofactor: NADPH-Regeneratingsystem (NRS) solution.; Time-points: 2, 12, 25, 45, and 65 minutes.

Reaction composition (in each incubation well) contains:

5 uL compound (50 uM stock solution, 50:50 ACN:H2O) 25 uL NRS solution6.25 uL 20 mg/mL liver microsomes 213.75 uL 100 mM KPO4, pH 7.4 250 uLtotal volume

At an incubation temperature of 37° C., the reaction was started withaddition of NADPH Regeneration System, at each time point, 25 uL of thereaction mixture was removed and added to a plate with 225 uL quenchingsolution (50% MeOH, 25 ACN, 25% H2O, and 200 nM labetalol as internalstandard). After plates were vortexed, they were centrifuged for 30minutes to remove proteins. About 100 μL supernatant was removed to anew plate and diluted with 150 μL water. About 20 μL of the mixture wasinjected into LC/MS/MS system to monitor the compound's response. Invitro measured t1/2 was used to calculate Clint values. Data ispresented in Table 1 below and FIG. 1.

TABLE 1 EC₅₀ Rat. Pred. Cl. Dog. Pred. Cl. Human Pred Cl. Cmpd (nM)(L/H/kg) (L/H/kg) (L/H/kg) 1 — — — 2 2.64 3 6.95 4 2.82 5 4.37 6 3.560.22 <0.11 7 3.61 0.21 <0.11 8 2.46 9 10.13 10 3.46 11 3.72 0.18 0.18 123.11 13 6.3 14 4.39 1.13 0.66 15 4.22 16 4.64 0.45 <0.11 17 7.24 18 51.03 0.13 19 8.43 0.29 <0.11 20 4.39 0.18 0.34 21 2.32 22 3.24 23 4.820.22 0.21 <0.11 24 3.82 25 3.19 1.41 0.16 26 4.24 1.6 <0.11 27 3.5 284.56 29 4.02 30 4.44 31 3.06 0.75 <0.11 32 2.65 0.59 <0.11 33 4.71 345.26 35 3.54 2.1 1.74 <0.11 36 3.68 0.27 <0.11 37 6.75 0.32 <0.11 386.13 39 2.57 0.54 0.15 40 3.89 0.5 0.13 41 3.58 42 3.18 43 2.87 1.011.66 0.16 44 3.97 2.54 0.13 45 2.56 0.92 <0.11 46 4.34 0.19 1.64 <0.1147 7.18 48 114.29 0.18 <0.11 49 37.3 50 4.31 <0.18 <0.11 51 2.8 <0.11 528.15 <0.18 0.14 53 2.98 0.2 0.51 54 8.47 55 4.44 56 3.59 0.19 1.47 0.1757 2.91 <0.18 <0.11 58 4.79 0.24 <0.11 59 3.38 0.83 0.6 60 3.42 0.650.12 61 4.11 <0.18 <0.11 62 8.83 63 4.25 0.2 0.86 <0.11 64 5.4 65 7.7 6614.52 67 6.25 1.43 0.41 68 7.25 0.61 <0.11 69 3.24 <0.18 <0.11 70 4.79<0.18 <0.11 71 3.37 <0.18 0.47 <0.11 72 5.19 <0.18 0.14 73 4.72 <0.180.13 74 6.79 0.2 1.53 0.17 75 3.41 0.21 <0.11 76 3.53 77 2.49 0.25 <0.1178 6.27 <0.18 <0.11 79 3.53 <0.18 <0.11 80 3.13 81 4.39 0.39 <0.11 824.4 0.44 0.82 83 17.25 84 3.23 85 3.78 0.19 0.13 86 2.61 <0.18 <0.11 874.26 0.23 0.13 88 4.57 <0.18 1.63 <0.11 89 3.32 <0.18 1.67 <0.11 90 3.450.67 0.14 91 3.69 92 3.72 93 2.49 1.13 0.19 94 2.57 95 2.44 1.39 0.38 962.33 97 4.54 0.31 0.46 98 4.97 0.65 0.26 99 7.96 0.26 <0.11 100 7.96 1014.22 <0.18 <0.11 102 5.68 <0.18 0.18 103 4.84 0.32 0.16 104 4.97 1053.16 0.39 106 4.04 107 2.23 1.1 108 7.23 109 59.71 110 30.8 111 7.22 1124.45 0.32 <0.11 113 6.01 114 5.1 0.28 <0.11 115 3.19 <0.18 0.12 116 2.790.39 0.19 117 4.15 118 10.61 119 3.66 0.27 1.35 <0.11 120 5.36 0.53 0.14121 3.31 <0.18 <0.11 122 4.57 <0.11 123 4.16 <0.18 <0.11 124 6.32 0.5<0.11 125 126 4.13 <0.18 0.45 127 4.19 1.3 0.54 128 3.16 0.37 0.15 1293.62 <0.11 130 3.41 <0.18 0.32 131 5.24 <0.11 132 18.24 133 3.44 <0.18<0.11 134 5.52 <0.18 <0.11 135 3.64 136 3.85 137 3.31 138 2.32 0.95 0.17139 3.92 140 5.09 141 6.68 142 8.78 143 7.79 144 5.12 0.95 145 5.06<0.11 146 8.17 <0.11 147 6.79 <0.11 148 6.95 149 8.3 150 5.86 151 4.82152 6.16 153 154 4.81 <0.18 <0.11 155 8.95 156 17.04 157 4.53 158 4.370.22 <0.11 159 3.83 <0.11 160 5700 161 14 <0.11 162 12.25 163 2.32 <0.11164 7.89 165 4.05 3.2 0.56 166 7.06 167 4.97 <0.11 168 5.48 2.42 0.19169 6.76 170 4.13 <0.18 <0.11 171 4.59 0.215 0.27 <0.11 172 5.86 1732.55 1.2 <0.11 174 2.33 0.69 0.18 175 2.17 0.7 0.67 176 3.36 0.75 <0.11177 8.12 178 10.32 179 3.55 0.27 0.33 180 3.69 <0.18 <0.11 181 8.5 1828.82 183 — — 184 3.66 <0.18 <0.11 185 2.58 0.31 0.32 186 4.74 <0.11 1874.7 188 9 189 5.47 190 7.06 191 17.42 192 2.89 0.36 1.04 0.22 193 2.78194 7.2 195 2.76 0.52 0.12 196 10.54 197 2.61 0.32 <0.11 198 2.19 0.33<0.11 199 2.72 0.48 0.91 <0.11 200 4.36 0.19 <0.11 201 2.67 0.49 0.27202 9.67 203 5.02 1.09 0.32 204 3.18 0.48 0.19 205 5.25 206 3.7 1.030.41 207 2.46 0.92 0.25 208 2.51 0.74 0.16 209 3.19 1.21 1.12 210 14.98<0.18 0.18 211 5.75 212 4.97 0.33 0.33 213 4.86 214 12.33 <0.18 <0.11215 18.21 216 114.29 217 113.31 218 2.99 0.45 0.92 219 4.1 0.24 0.19<0.11 220 7.66 0.34 0.46 <0.11 221 4.49 0.28 0.14 <0.11 222 12.93 22312.88 224 4.12 225 4.26 226 14.93 227 2.9 228 1.66 229 7.86 0.26 <0.11230 3.97 231 2.77 232 2.47 233 2.71 <0.18 <0.11 234 2.54 235 16.74 23637.03 237 4.89 238 12.3 239 4.45 <0.18 <0.11 240 5.62 241 6.57 242 3.45243 5.32 244 19.53 245 3.59 DRV 2.8 1.2 1.2 ATV 3.7 1.4 1.07

3H Human Predicted Clearance Assay:

For certain compounds, tritiated analogs (H³) were prepared to furtherdetermined their human predicted clearance with increased resolution.Those studies were performed as described above using the tritiatedanalogs. Data from those compounds is found in Table 2 below andreported in FIG. 1 (note ATV and DRV were not tritiated).

TABLE 2 Compound 3H Human Predicted Cl. 23 0.07 36 0.1 46 0.04 51 0.1158 0.05 88 0.08 73 0.09 75 0.11 89 0.08 101 0.08 112 0.11 153 0.43 1700.05 171 0.02 173 0.14 176 0.09 199 0.15 208 0.11 239 0.13

Pharmacokinetic Profiling

Dog PK

Test compound was formulated in 5% EtOH, 55% PEG 300 and 40% Water (pH2, HCl) for IV infusion administration and was formulated in 5% Ethanol,55% PEG 300, 1% Tween 80 and 39% water (pH 2) for oral dosing. Eachdosing group consisted of three non-naïve male beagle dogs. At dosing,the animals weighed between 9 to 12 kg. The animals were fastedovernight prior to dose administration and up to four hours afterdosing. The test article was administered by intravenous infusion over30-minutes. The rate of infusion was adjusted according to the bodyweight of each animal to deliver a dose of 0.5 or 1.0 mg/kg. For theoral dosing group, the test article was administered by oral gavage at adose volume of 2 mL/kg.

Serial venous blood samples (approximately 1.0 mL each) were collectedat predose and 0.25, 0.48, 0.58, 0.75, 1.0, 1.5, 2, 4, 8, 12 and 24hours post dose from each animal for the IV dosing group; blood sampleswere collected at predose, 0.25, 0.50, 1,2 4, 6, 8,12 and 24 hours postdose for the oral dosing group. The blood samples were collected intoVacutainer™ tubes containing EDTA-K2 as the anti-coagulant and wereimmediately placed on wet ice pending centrifugation for plasma. AnLC/MS/MS method was used to measure the concentration of test compoundin plasma. Non-compartmental pharmacokinetic analysis was performed onthe plasma concentration-time data. Data for certain compounds arereported in FIG. 2 and Table 3 below. VSS =apparent volume ofdistribution, t1/2=half life, F=oral bioavailability.

TABLE 3 DOG IV DOG IV DOG IV DOG PO DOG PO Com- CL VSS T½ F DOSE pound(L/HR/KG) (L/KG) (HR) (%) (mg/kg) 58 0.47 6.34 13.8 18 2 63 0.28 2.48.16 170 1.39 4.35 7.62 2.45 2 171 0.26 3.12 13.4 23 2 DRV 2.7 0.87 0.3738 2 ATV 1.0 0.90 1.3 48 10

Rat PK:

Test article was formulated in 5% Ethanol, 55% PEG 300 and 40% Water (pH2) for IV infusion administration and was formulated in 5% Ethanol, 55%PEG 300, 1% Tween 80 and 39% water (pH 2) for oral administration. Eachdosing group consisted of 3 male naive SD Rats. At dosing, the animalsweighed between 0.27 to 0.32 kg. The animals were fasted overnight priorto dose administration. The test article was administered by intravenousinfusion over 30 min. The rate of infusion was adjusted according to thebody weight of each animal to deliver a dose of 0.5 or 1.0 mg/kg. Forthe oral dosing group, the test article was administered to animals byoral gavage administration. Serial venous blood samples (approximately0.30 mL each) were taken at predose and 0.25, 0.48, 0.58, 0.75, 1.5, 3,6, 8, 12 and 24 hours post dose for the IV dosing group animals. Bloodsamples were taken at predose, 0.25, 0.50, 1, 2, 4, 6, 8, 12 and 24hours post dose for the oral group animals. The blood samples werecollected into Vacutainer™ tubes containing EDTA-K2 as theanti-coagulant and were immediately placed on wet ice pendingcentrifugation for plasma. An LC/MS/MS method was used to measure theconcentration of test compound in plasma. Non-compartmentalpharmacokinetic analysis was performed on the plasma concentration-timedata.

Data for certain compounds are reported in Table 4 and FIG. 3accordingly.

TABLE 4 RAT IV RAT IV RAT IV RAT PO RAT PO Com- CL VSS T 1/2  F DOSEpound (L/HR/KG) (L/KG) (HR) (%) (mg/kg) 36 0.32 5.99 15.7 16.4 2.5 460.45 4.22 9.22 13 2.5 56 0.85 7.44 8.77 34.1 2.5 57 0.36 2.45 6.28 23.22.5 58 0.48 6.68 12.8 37.2 2.5 61 0.43 6.5 12.9 18.5 2.5 63 0.42 5.4611.9 19 2.5 71 0.9 7.26 9.27 24.6 2.5 73 0.32 3.34 9.43 35 2.5 74 0.395.07 11.6 35.8 2.5 79 0.77 4.07 5.13 13.1 2.5 89 0.3 3.53 10.2 44.2 2.5101 0.48 6.07 10 38.4 2.5 130 0.39 5.27 11.5 55.7 2.5 170 0.35 3.32 9.3836.6 2.5 171 0.32 8.11 22.5 39 2.5 180 0.39 0.52 2.81 4.29 2.5 199 0.461.07 2.09 14.7 2.5 221 0.32 4.41 11.5 19.9 2.5 239 0.4 5.49 12.9 26.32.5 DRV 2.2 0.73 0.32 24 2.0 ATV 2.7 0.87 0.37 38 5.0

Protease Resistance Screening.

Drug EC₅₀ values versus PI resistant mutant viruses for certaincompounds were determined in a 5-day multi-cycle cell viability assaymeasuring protection from cytopathic effect (CPE). Briefly, MT-2 cellswere bulk infected at a density of 2×10⁶ cells/mL with WT or mutantviruses at a multiplicity of infection (MOI) of 0.01 by gently rockingthe culture for 3 hours at 37° C. and then added in triplicate to96-well plates (Corning Life Sciences, Tewksbury, Mass., USA). Cellswere incubated in complete RPMI medium containing a 10-point, 3-foldserial drug dilution (0.5% final DMSO concentration) for five days at37° C. in 5% CO₂. After this time, 100 μL of CellTiter-Glo reagent(Promega, Madison, Wis., USA) was added to each well and theluminescence signals quantified on an EnVision plate reader(Perkin-Elmer, Inc., Waltham, Mass., USA). EC₅₀ values, defined as thedrug concentration inducing a 50% protection from HIV-induced cellkilling, were calculated from a minimum of three independent experimentsperformed in quadruplicate using XLFit™ software (IDBS, Ltd., Guildford,Surrey, UK) and nonlinear regression analysis. As an illustrativeexample, data associated with the compound of Example 58 (GSPI1) ispresented in FIG. 4 below as compared to other HIV protease inibitors(atazanavir and darunavir).

MT-2 Cell Viral Breakthrough Assay.

MT-2 cells were infected with HIV-1_(IIIB) (Advanced Biotechnologies,Eldersburg, Md., USA) at a relatively high multiplicity of infection(MOI=0.05) for 3 hours and plated in 24-well plates at 2×10⁵ cells perwell. Drugs were added 16 hours later to a minimum of quadruplicatewells at fixed multiples of their EC₅₀ values. Every 3-4 days, cellswere diluted (1:5) into freshly prepared cell culture media containingdrug concentrations at the same multiple of EC₅₀ values and monitoredfor virus-induced cytopathic effects (CPE) over a period of 32 days.Cell-free viral supernatants were harvested from wells showing >80% CPEand kept frozen at −80° C. until further analyzed. As an illustrativeexample, data associated with the compound of Example 58 (GSPI1) ispresented in FIG. 5 below as compared to other HIV protease inibitors(atazanavir, darunavir) and efavirenz.

Genotypic Analysis Of Breakthrough Viruses.

Total RNA was purified from the cell-free supernatants obtained fromeach CPE-positive and p24-positive well using the Qiagen Viral RNAIsolation kit (Qiagen, Valencia, Calif., USA). The coding regionstargeted by each drug were amplified by One-Step RT-PCR (Qiagen) and theproducts subjected to DNA sequencing. Sequence changes were identifiedby alignment with input virus sequences using Sequencher (Gene CodesCorp., Ann Arbor, Mich., USA) and amino acid substitutions determined.

Equilibrium Dialysis Assay

Pooled plasma (from at least 3 males and 3 females) was fromBioreclamation IVT. Sodium EDTA was used as the anticoagulant. 10%plasma was diluted in in 0.133M phosphate buffer consisted of 1.5% (w/v)Sodium EDTA.

RPMI cell culture media consisted 10% FBS was provided by biologydepartment, Gilead Sciences, Inc.

Plasma protein binding assay: Studies were conducted in duplicate ortriplicate using a Dianorm Equilibrium Dialyser (Harvard Apparatus,Holliston Mass.) with each cell consisting of a semipermeable membrane(2.4 cm working diameter) separating two 1 mL PTFE half-cells (Weder HG, Schildknecht J, Kesselring P. A new equilibrium dialyzing system.American Laboratory. 1971; 10: 15-21). Prior to the study, the dialysismembrane was soaked for approximately one hour in 0.133 M phosphatebuffer, pH 7.4. 10% plasma and cell culture media spiked with 1 μMcompound (1 mL) were placed into opposite sides of the assembleddialysis cells and the dialysis cells were then rotated slowly in a 37°C. water bath. After the equilibration period, matrix-containing samplesfrom both sides were drained into pre-weighed polypropylene tubes.Post-dialysis 10% plasma samples were transferred into centrifuge tubescontaining 1mL of blank cell culture media. Post-dialysis cell culturemedia samples were transferred into centrifuge tubes containing 1 mL ofblank 10% plasma. All samples weights were measured and recorded forcalculations of volume shift and recovery.

Samples were deproteinated by treatment with four volumes of 90% (v/v)acetonitrile, 10% (v/v) methanol containing the LC-MS internal standard.Samples were centrifuged 15,000 rpm at 4° C. for 15 min and 200 μLaliquots of the supernatants removed and mixed with an equal volume ofwater. Samples were vortexed for 2 min, and then aliquots (10 μL)subject to LC-MS/MS analysis.

Data Analysis

The binding ratio for an analyte in plasma vs. cell culture media wascalculated using the following equations:

Ratio=C ₁₀% plasma/C _(CCM)

where C_(10% plasma) is the post-dialysis 10% plasma concentration(determined by PAR), and C_(CCM) is the post-dialysis cell culture mediaconcentration (determined by PAR), respectively. Each concentration wascorrected gravimetrically for changes in liquid volume in the dialysiscells occurring during dialysis.

Protease Ki Assay

Inhibitor potency was measured using an enzymatic assay with afluorogenic readout. To a reaction buffer containing 100 mM ammoniumacetate at pH 5.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.25 mg/mL BSA and1% DMSO were added 2.5 nM of recombinant HIV protease and test compoundat one of various concentrations. After a 20-minute pre-incubation, theenzymatic reaction was initiated by the addition of the fluorogenicsubstrate (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg (Bachem) to afinal concentration of 40 μM. The total volume of the assay solution was100 □L. The reaction was measured over 20 minutes on a Tecan InfiniteM1000 plate reader using an excitation wavelength of 320 nm and adetection wavelength of 420 nm. The slopes of the progress curves werethe measure of reaction rates. Reaction rates were plotted as a functionof inhibitor concentration, and the data were fit using thetight-binding equation described by Morrison (Biochim. Biophys. Acta1969, 185, 269-286) to yield K_(i) values.

TABLE 5 Potency of Compound 58, DRY, and ATV Compound 58 darunaviratazanavir Ki (nM) 0.060 <0.030 0.035 EC₅₀ (nM) 6.8 7.2 9.7Hill-coefficient 5.8 2.9 3.1 EC₉₅ (nM) 11.4 19.9 25 Protein Adjusted 35342 75 EC₉₅ (nM)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a 5 to10-membered heterocycle having 1 to 5 heteroatoms selected from N, O,and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatomsselected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5to 10-membered heteroaryl is optionally substituted with 1 to 5 R^(a)groups; R² and R³ are each independently C₁₋₄alkyl, C₃₋₆cycloalkyl,O—R^(2A), C₁₋₂alkyl-O—R^(2A), N-(R^(3A))₂, or C₁₋₂alkyl-N-(R^(3A))₂,wherein each R^(2A) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N,O, and S, wherein each R^(3A) is independently hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl, or COO(R^(c)), and wherein each C₃₋₆cycloalkyl or 4 to10-membered heterocyclyl is optionally substituted by 1 to 3 R^(f)groups, wherein each R^(f) is independently C₁₋₂alkyl or halogen; R⁴ ishydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, orC₁₋₄haloalkoxy; R⁷ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, C₁₋₄alkoxy, or C₁₋₄haloalkoxy; R⁵, R⁶, R⁸, and R⁹ areeach independently hydrogen, halo, C₁₋₂alkyl, C₁₋₂haloalkyl, orC₃₋₆cycloalkyl; and wherein two or more of R⁴, R⁵ and R⁶ or two or moreof R⁷, R⁸, and R⁹ optionally join together to form one or moreC₃₋₆cycloalkyl groups that are optionally substituted with 1 to 4 groupsselected from halogen, C₁₋₂alkyl, and C₁₋₂haloalkyl; each R¹⁰ isindependently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, or C₃₋₆cycloalkyl;n is 0 to 4; each R^(a) is independently halogen, C₁₋₄alkyl, C₁₋₄alkylsubstituted with 1 to 2 groups selected from hydroxyl and C₁₋₄alkoxy,C₁₋₄haloalkyl, C₁₋₄alkoxy, C3-6 cycloalkyl, 4 to 10-memberedheterocyclyl having 1 to 5 heteroatoms selected from N, O, and S whichis optionally substituted with R^(a1), or O—R^(3B), wherein R^(3B) isC₃₋₆cycloalkyl optionally substituted with R^(a1) or a 4 to 10-memberedheterocyclyl having 1 to 5 heteroatoms selected from N, O, and Soptionally substituted with R^(a1), wherein each R^(a1) is independentlyC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄haloalkyl, or 4 to 8-memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; A isethynyl or a bond; X¹ is a 6 to 10-membered aryl or a 5 to 10-memberedheteroaryl having 1 to 3 heteroatoms selected from N, O, and S, whereineach 6 to 10-membered aryl or 5 to 10-membered heteroaryl is optionallysubstituted with 1 to 4 R^(b) groups; X² is hydrogen or a 4 to10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O,and S, wherein the 4 to 10-membered heterocyclyl is optionallysubstituted with one R¹¹ and optionally substituted with 1 to 5 R^(b)groups; R¹¹ is C═O(R^(c)), CH₂(R^(d)), S(O)₁₋₂(C₁₋₄alkyl),S(O)₁₋₂C₃₋₆cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5heteroatoms selected from N, O, and S, or a 5 to 9-membered heteroarylhaving 1 to 5 heteroatoms selected from N, O, and S, wherein each 4 to10-membered heterocyclyl or 5 to 9-membered heteroaryl is optionallysubstituted with 1 to 5 R^(b) groups; each R^(b) is independentlyhalogen, oxo, C₁₋₄alkyl, C₁₋₄alkyl substituted with 1 to 2 groupsselected from hydroxyl and C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄alkoxy, orCOO(R^(e)); R^(e) is C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, N(R^(e))₂,C₃₋₆cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, wherein the C₃₋₆cycloalkyl andthe 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5R^(b) groups; R^(d) is COO(R^(e)), N(R^(e))₂, C₃₋₆cycloalkyl, or a 4 to6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O,and S, wherein the C₃₋₆cycloalkyl and the 4 to 6-membered heterocyclylis optionally substituted by 1 to 5 R^(b) groups; each R¹² is C₁₋₂alkyl,halo, —OC₁₋₂alkyl, or cyano; each p is 0 to 4; and each R^(e) isindependently hydrogen or C₁₋₄alkyl.
 2. The compound of claim 1, whereinR² and R³ are each independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or O—R^(2A),wherein R^(2A) is C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4 to 10-memberedheterocyclyl having 1 to 5 heteroatoms selected from N, O, and S.
 3. Thecompound of claim 1, wherein R² and R³ are each independently:


4. The compound of claim 1, wherein R² and R³ are each methoxy.
 5. Thecompound of claim 1, wherein R⁴ is hydrogen, C₁₋₄alkyl, orC₁₋₄haloalkyl.
 6. The compound of claim 1, wherein R⁴ is C₁₋₄haloalkyl.7. The compound of claim 1, wherein R⁴ is CF₃.
 8. The compound of claim1, wherein R⁷ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl.
 9. The compoundof claim 1, wherein R⁷ is C₁₋₄haloalkyl.
 10. The compound of claim 1,wherein R⁷ is CF₃.
 11. The compound of claim 1, wherein R⁵ and R⁶ areC₁₋₂alkyl.
 12. The compound of claim 1, wherein R⁵ and R⁶ are methyl.13. The compound of claim 1, wherein R⁸ and R⁹ are C₁₋₂alkyl.
 14. Thecompound of claim 1, wherein R⁸ and R⁹ are methyl.
 15. The compound ofclaim 1, wherein n is
 2. 16. The compound of claim 1, wherein each R¹⁰is halogen.
 17. The compound of claim 1, wherein each R¹⁰ is fluoro. 18.The compound of claim 1, wherein A is ethynyl.
 19. The compound of claim1, wherein R¹ is a 5 to 6-membered heterocycle having 1 to 3 heteroatomsselected from N, O, and S, or a 5 to 6-membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S, wherein the 5 to 6-memberedheterocycle or 5 to 6-membered heteroaryl is optionally substituted with1 to 3 R^(a) groups.
 20. The compound of claim 1, wherein R¹ is a 5 to6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, andS and is optionally substituted with 1 to 3 R^(a) groups.
 21. Thecompound of claim 1, wherein R¹ is independently:


22. The compound of claim 1, wherein R¹ is:


23. The compound of claim 1, wherein R^(a) is independently C₁₋₄alkyl,C₁₋₄alkyl with 1 to 2 groups selected from hydroxyl and C₁₋₄alkoxy, orC₁₋₄haloalkyl.
 24. The compound of claim 1, wherein R^(a) is:


25. The compound of claim 1, wherein R^(a) is C₁₋₄haloalkyl.
 26. Thecompound of claim 1, wherein R^(a) is:


27. The compound of claim 1, wherein X¹ is a 6-membered aryl or a 5 to6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, andS, wherein each 6-membered aryl or 5 to 6-membered heteroaryl isoptionally substituted with 1 to 4 R^(b) groups.
 28. The compound ofclaim 1, wherein X¹ is pyrimidine or pyridine.
 29. The compound of claim1, wherein X¹ is:


30. The compound of claim 1 wherein X² is a 4 to 10-memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S and isoptionally substituted with one R¹¹ and optionally substituted with 1 to5 R^(b) groups.
 31. The compound of claim 1, wherein X² is

wherein: a) R^(P1), R^(P2), R^(P3), and R^(P4) are each hydrogen; b)R^(P1) and R^(P3) are taken together to form a —CH₂— or —CH₂CH₂— groupand R^(P2) and R^(P4) are each hydrogen; c) R^(P2) and R^(P4) are takentogether to form a —CH₂— or —CH₂CH₂— group and R^(P1) and R^(P3) areeach hydrogen. d) R^(P1) and R^(P4) are taken together to form a —CH₂—group and R^(P2) and R^(P3) are each hydrogen; or e) R^(P2) and R^(P3)are taken together to form a —CH₂— group and R^(P1) and R^(P4) are eachhydrogen.
 32. The compound of claim 31, wherein: R^(P1) and R^(P3) aretaken together to form a —CH₂— or —CH₂CH₂— group and R^(P2) and R^(P4)are each hydrogen; or R^(P2) and R^(P4) are taken together to form a—CH₂— or —CH₂CH₂— group and R^(P)' and R^(P3) are each hydrogen.
 33. Thecompound of claim 1, wherein X² is:


34. The compound of claim 1, wherein X² is:


35. The compound of claim 1, wherein R¹¹ is 4 to 10-memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S. 36.The compound of claim 1, wherein R¹¹ is a 4 to 6-membered heterocyclehaving one oxygen.
 37. The compound of claim 1, wherein R¹¹ isoxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.
 38. Thecompound of claim 1, wherein p is
 0. 39-43. (canceled)
 44. The compoundof claim 1, wherein A is a bond.
 45. A compound of any of Examples1-245, or a pharmaceutically acceptable salt thereof.
 46. The compoundof claim 1, selected from:

or a pharmaceutically acceptable salt thereof. 47-57. (canceled)
 58. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.
 59. The pharmaceuticalcomposition of claim 58, further comprising one, two, three, or fouradditional therapeutic agents. 60-63. (canceled)
 64. A method oftreating a human immunodeficiency virus (HIV) infection comprisingadministering a therapeutically effective amount of a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a 5 to10-membered heterocycle having 1 to 5 heteroatoms selected from N, O,and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatomsselected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5to 10-membered heteroaryl is optionally substituted with 1 to 5 R^(a)groups; R² and R³ are each independently C₁₋₄alkyl, C₃₋₆cycloalkyl,O—R^(2A), C₁₋₂alkyl-O—R^(2A), N-(R^(3A))₂, or C₁₋₂alkyl-N-(R^(3A))₂,wherein each R^(2A) is independently C₁₋₄alkyl, C₃₋₆cycloalkyl, or a 4to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N,O, and S, wherein each R^(3A) is independently hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl, or COO(R^(e)), and wherein each C₃₋₆cycloalkyl or 4 to10-membered heterocyclyl is optionally substituted by 1 to 3 R^(f)groups, wherein each R^(f) is independently C₁₋₂alkyl or halogen; R⁴ ishydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, orC₁₋₄haloalkoxy; R⁷ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, C₁₋₄alkoxy, or C₁₋₄haloalkoxy; R⁵, R⁶, R⁸, and R⁹ areeach independently hydrogen, halo, C₁₋₂alkyl, C₁₋₂haloalkyl, orC₃₋₆cycloalkyl; and wherein two or more of R⁴, R⁵ and R⁶ or two or moreof R⁷, R⁸, and R⁹ optionally join together to form one or moreC₃₋₆cycloalkyl groups that are optionally substituted with 1 to 4 groupsselected from halogen, C₁₋₂alkyl, and C₁₋₂haloalkyl; each R¹⁰ isindependently halogen, cyano, C₁₋₄alkoxy, C₁₋₆alkyl, or C₃₋₆cycloalkyl;n is 0 to 4; each R^(a) is independently halogen, C₁₋₄alkyl, C₁₋₄alkylsubstituted with 1 to 2 groups selected from hydroxyl and C₁₋₄alkoxy,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₃₋₆cycloalkyl, 4 to 10-membered heterocyclylhaving 1 to 5 heteroatoms selected from N, O, and S which is optionallysubstituted with R^(a1), or O—R^(3B), wherein R^(3B) is C₃₋₆cycloalkyloptionally substituted with R^(a1) or a 4 to 10-membered heterocyclylhaving 1 to 5 heteroatoms selected from N, O, and S optionallysubstituted with R^(a1), wherein each R^(a1) is independently C₁₋₄alkyl,C₃₋₆cycloalkyl, C₁₋₄haloalkyl, or 4 to 8-membered heterocyclyl having 1to 3 heteroatoms selected from N, O, and S; A is ethynyl or a bond; X¹is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl having 1 to3 heteroatoms selected from N, O, and S, wherein each 6 to 10-memberedaryl or 5 to 10-membered heteroaryl is optionally substituted with 1 to4 R^(b) groups; X² is hydrogen or a 4 to 10-membered heterocyclyl having1 to 5 heteroatoms selected from N, O, and S, wherein the 4 to10-membered heterocyclyl is optionally substituted with one R¹¹ andoptionally substituted with 1 to 5 R^(b) groups; R¹¹ is C═O(R^(c)),CH₂(R^(d)), S(O)₁₋₂(C₁₋₄alkyl), S(O)₁₋₂C₃₋₆cycloalkyl, a 4 to10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O,and S, or a 5 to 9-membered heteroaryl having 1 to 5 heteroatomsselected from N, O, and S, wherein each 4 to 10-membered heterocyclyl or5 to 9-membered heteroaryl is optionally substituted with 1 to 5 R^(b)groups; each R^(b) is independently halogen, oxo, C₁₋₄alkyl, C₁₋₄alkylsubstituted with 1 to 2 groups selected from hydroxyl and C₁₋₄alkoxy,C₁₋₄haloalkyl, C₁₋₄alkoxy, or COO(R^(e)); R^(c) is C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, N(R^(e))₂, C₃₋₆cycloalkyl, or a 4 to6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O,and S, wherein the C₃₋₆cycloalkyl and the 4 to 6-membered heterocyclylare optionally substituted by 1 to 5 R^(b) groups; R^(d) is COO(R^(e)),N(R^(e))₂ C₃₋₆ cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to3 heteroatoms selected from N, O, and S, wherein the C₃₋₆cycloalkyl andthe 4 to 6-membered heterocyclyl is optionally substituted by 1 to 5R^(b) groups; each R¹² is C₁₋₂alkyl, halo, —OC₁₋₂alkyl, or cyano; each pis 0 to 4; and each R^(e) is independently hydrogen or C₁₋₄alkyl, or apharmaceutically acceptable salt thereof, to a subject in need thereof.65. The method of claim 64, wherein the method comprises administeringthe compound, or a pharmaceutically acceptable salt thereof, incombination with one, two, three, or four additional therapeutic agents.66-101. (canceled)